Potential of a cyclone prototype spacer to improve in vitro dry powder delivery

Copyright The Author(s) 2013. This article is published with open access at Springerlink.com. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are creditedPurpose: Low inspiratory force in patients with lung disease is associated with poor deagglomeration and high throat deposition when using dry powder inhalers (DPIs). The potential of two reverse flow cyclone prototypes as spacers for commercial carrierbased DPIs was investigated. Methods: Cyclohaler®, Accuhaler® and Easyhaler® were tested with and without the spacers between 30-60 Lmin-1. Deposition of particles in the next generation impactor and within the devices was determined by high performance liquid chromatography. Results: Reduced induction port deposition of the emitted particles from the cyclones was observed due to the high retention of the drug within the spacers (e.g. salbutamol sulphate (SS): 67.89 ± 6.51 % at 30 Lmin-1 in Cheng 1). Fine particle fractions of aerosol as emitted from the cyclones were substantially higher than the DPIs alone. Moreover, the aerodynamic diameters of particles emitted from the cyclones were halved compared to the DPIs alone (e.g. SS from the Cyclohaler® at 4 kPa: 1.08 ± 0.05 μm vs. 3.00 ± 0.12 μm, with and without Cheng 2, respectively) and unaltered with increased flow rates. Conclusion: This work has shown the potential of employing a cyclone spacer for commercial carrier-based DPIs to improve inhaled drug delivery.Peer reviewe

Evaluation and Management of Anal Intraepithelial Neoplasia in HIV-Negative and HIV-Positive Men Who Have Sex with Men

The incidence of human papillomavirus (HPV)–associated anal cancer in men who have sex with men (MSM) is striking and has not been mitigated by the use of highly active antiretroviral therapy. Detection and treatment of high-grade anal intraepithelial neoplasia (HGAIN) may reduce the incidence of anal cancer. Anal cytology is a useful tool to detect HGAIN; annual screening of HIV-positive MSM and biennial screening of HIV-negative MSM appears to be cost-effective. MSM with abnormal cytology should be referred for high-resolution anoscopy and biopsy. Individuals with HGAIN should receive treatment; treatment modalities for HGAIN demonstrate moderate efficacy and are usually well tolerated, but greater study is required to determine which treatment is optimal. Large prospective studies are needed to document the efficacy of screening and treatment of HGAIN on anal cancer incidence. The HPV vaccine holds promise for primary prevention of anal cancer in MSM, but significant implementation challenges remain

Early Stage Biomineralization in the Periostracum of the ‘Living Fossil’ Bivalve Neotrigonia

A detailed investigation of the shell formation of the palaeoheterodont ‘living fossil’ Neotrigonia concentrated on the timing and manufacture of the calcified ‘bosses’ which stud the outside of all trigonioid bivalves (extant and fossil) has been conducted. Electron microscopy and optical microscopy revealed that Neotrigonia spp. have a spiral-shaped periostracal groove. The periostracum itself is secreted by the basal cell, as a thin dark pellicle, becoming progressively transformed into a thin dark layer by additions of secretions from the internal outer mantle fold. Later, intense secretion of the internal surface of the outer mantle fold forms a translucent layer, which becomes transformed by tanning into a dark layer. The initiation of calcified bosses occurred at a very early stage of periostracum formation, deep within the periostracal groove immediately below the initialmost dark layer. At this stage, they consist of a series of polycyclically twinned crystals. The bosses grow as the periostracum traverse through the periostracal groove, in coordination with the thickening of the dark periostracal layer and until, upon reaching the mantle edge, they impinge upon each other and become transformed into large prisms separated by dark periostracal walls. In conclusion, the initial bosses and the external part of the prismatic layer are fully intraperiostracal. With later growth, the prisms transform into fibrous aggregates, although the details of the process are unknown. This reinforces the relationships with other groups that have the ability to form intraperiostracal calcifications, for example the unionoids with which the trigonioids form the clade Paleoheterodonta. The presence of similar structures in anomalodesmatans and other euheterodonts raises the question of whether this indicates a relationship or represents a convergence. The identification of very early calcification within an organic sheet has interesting implications for our understanding of how shells may have evolved.Coordinated Research Projects CGL2010-20748-C02-01 (AGC, EMH) and 02 (CS) (DGI, Spanish MICINN); the Research Group RNM363 (Consejería de Economía, Investigación, Ciencia y Empleo, Junta de Andalucía); and the FP7 COST Action TD0903 of the European Community

Mitogen- and Stress-Activated Kinase 1 (MSK1) Regulates Cigarette Smoke-Induced Histone Modifications on NF-κB-dependent Genes

Cigarette smoke (CS) causes sustained lung inflammation, which is an important event in the pathogenesis of chronic obstructive pulmonary disease (COPD). We have previously reported that IKKα (I kappaB kinase alpha) plays a key role in CS-induced pro-inflammatory gene transcription by chromatin modifications; however, the underlying role of downstream signaling kinase is not known. Mitogen- and stress-activated kinase 1 (MSK1) serves as a specific downstream NF-κB RelA/p65 kinase, mediating transcriptional activation of NF-κB-dependent pro-inflammatory genes. The role of MSK1 in nuclear signaling and chromatin modifications is not known, particularly in response to environmental stimuli. We hypothesized that MSK1 regulates chromatin modifications of pro-inflammatory gene promoters in response to CS. Here, we report that CS extract activates MSK1 in human lung epithelial (H292 and BEAS-2B) cell lines, human primary small airway epithelial cells (SAEC), and in mouse lung, resulting in phosphorylation of nuclear MSK1 (Thr581), phospho-acetylation of RelA/p65 at Ser276 and Lys310 respectively. This event was associated with phospho-acetylation of histone H3 (Ser10/Lys9) and acetylation of histone H4 (Lys12). MSK1 N- and C-terminal kinase-dead mutants, MSK1 siRNA-mediated knock-down in transiently transfected H292 cells, and MSK1 stable knock-down mouse embryonic fibroblasts significantly reduced CS extract-induced MSK1, NF-κB RelA/p65 activation, and posttranslational modifications of histones. CS extract/CS promotes the direct interaction of MSK1 with RelA/p65 and p300 in epithelial cells and in mouse lung. Furthermore, CS-mediated recruitment of MSK1 and its substrates to the promoters of NF-κB-dependent pro-inflammatory genes leads to transcriptional activation, as determined by chromatin immunoprecipitation. Thus, MSK1 is an important downstream kinase involved in CS-induced NF-κB activation and chromatin modifications, which have implications in pathogenesis of COPD

VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation

Abstract Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS patients. We show that monocytes from VEXAS are quantitatively and qualitatively impaired and display features of exhaustion with aberrant expression of chemokine receptors. In peripheral blood from VEXAS patients, we identify an increase in circulating levels of many proinflammatory cytokines, including IL-1β and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirms these findings and also reveals a significant enrichment of TNF-α and NFκB signaling pathways that can mediate cell death and inflammation. This study suggests that the control of the nflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome