Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation

Edema occurs in asthma and other inflammatory diseases when the rate of plasma leakage from blood vessels exceeds the drainage through lymphatic vessels and other routes. It is unclear to what extent lymphatic vessels grow to compensate for increased leakage during inflammation and what drives the lymphangiogenesis that does occur. We addressed these issues in mouse models of (a) chronic respiratory tract infection with Mycoplasma pulmonis and (b) adenoviral transduction of airway epithelium with VEGF family growth factors. Blood vessel remodeling and lymphangiogenesis were both robust in infected airways. Inhibition of VEGFR-3 signaling completely prevented the growth of lymphatic vessels but not blood vessels. Lack of lymphatic growth exaggerated mucosal edema and reduced the hypertrophy of draining lymph nodes. Airway dendritic cells, macrophages, neutrophils, and epithelial cells expressed the VEGFR-3 ligands VEGF-C or VEGF-D. Adenoviral delivery of either VEGF-C or VEGF-D evoked lymphangiogenesis without angiogenesis, whereas adenoviral VEGF had the opposite effect. After antibiotic treatment of the infection, inflammation and remodeling of blood vessels quickly subsided, but lymphatic vessels persisted. Together, these findings suggest that when lymphangiogenesis is impaired, airway inflammation may lead to bronchial lymphedema and exaggerated airflow obstruction. Correction of defective lymphangiogenesis may benefit the treatment of asthma and other inflammatory airway diseases.     

Specific inhibition of secreted NRG1 types I–II by heparin enhances Schwann Cell myelination

Primary cultures of mixed neuron and Schwann cells prepared from dorsal root ganglia (DRG) are extensively used as a model to study myelination. These dissociated DRG cultures have the particular advantage of bypassing the difficulty in purifying mouse Schwann cells, which is often required when using mutant mice. However, the drawback of this experimental system is that it yields low amounts of myelin. Here we report a simple and efficient method to enhance myelination in vitro. We show that the addition of heparin or low molecular weight heparin to mixed DRG cultures markedly increases Schwann cells myelination. The myelin promoting activity of heparin results from specific inhibition of the soluble immunoglobulin (Ig)‐containing isoforms of neuregulin 1 (i.e., NRG1 types I and II) that negatively regulates myelination. Heparin supplement provides a robust and reproducible method to increase myelination in a simple and commonly used culture system. GLIA 2016;64:1227–1234     

The effect of central corneal thickness on Goldmann tonometry: a retrospective study

International Ophthalmology - To determine the relation between central corneal thickness and intraocular pressure. This retrospective study investigated 112 eyes from 56 individuals who underwent...     

A randomised trial of oral versus intravenous opioids for treatment of pain after cardiac surgery

Background

Cardiac surgery and sternotomy are procedures accompanied by substantial postoperative pain which is challenging to treat. In general, intravenous (IV) opioids are used in the immediate postoperative phase, followed by oral opioids. Oral opioids are easier to use and generally less expensive. Our goal was thus to determine whether a new opioid preparation provides adequate analgesia after sternotomy. In particular, we tested the primary hypothesis that total opioid use (in morphine equivalents) is not greater with oral opioid compared with patient-controlled IV morphine. Our secondary hypothesis was that analgesic efficacy is similar with oral and IV opioids.

Methods

A total of 51 patients having elective cardiac surgery were enrolled in this study. After rapid postoperative respiratory weaning, the patients were randomised into one of two groups receiving different types of analgesia: oral Targin (a combination of oxycodone–hydrochloride and the opioid antagonist naloxone hydrochloride-dihydrate) or patient-controlled IV morphine. Pain score (visual analogue scale), sedation (Ramsey score), respiratory rate and side effects were assessed at 3, 5, 7, 9 and 11 h after surgery, and every 6 h throughout the third postoperative evening.

Results

The total opioid dose in morphine equivalent doses was significantly lower with oral opioid than with IV morphine (adjusted geometric means [95 % confidence interval]: 34 [29; 38] vs. 69 [61; 78] mg, respectively). Pain scores were similar in each group.

Conclusions

Analgesic quality was comparable with oral and IV opioids, suggesting that postoperative pain even after very painful procedures can be sufficiently managed with oral opioids.     

Antimicrobial drug resistance mechanisms among Mollicutes

Representatives of the Mollicutes class are the smallest, wall-less bacteria capable of independent reproduction. They are widespread in nature, most are commensals, and some are pathogens of humans, animals and plants. They are also the main contaminants of cell cultures and vaccine preparations. Despite limited biosynthetic capabilities, they are highly adaptable and capable of surviving under various stress and extreme conditions, including antimicrobial selective pressure. This review describes current understanding of antibiotic resistance (ABR) mechanisms in Mollicutes. Protective mechanisms in these bacteria include point mutations, which may include non-target genes, and unique gene exchange mechanisms, contributing to transfer of ABR genes. Better understanding of the mechanisms of emergence and dissemination of ABR in Mollicutes is crucial to control these hypermutable bacteria and prevent the occurrence of highly ABR strains.     

General Ser/Thr Kinases Pharmacophore Approach for Selective Kinase Inhibitors Search as Exemplified by Design of Potent and Selective Aurora A Inhibitors

A general pharmachophore model for various types of Ser/Thr kinases was developed. Search for the molecules fitting to this pharmacophore among ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against several Ser/Thr kinases such as Aurora A, Aurora B and Haspin. The possibility of performing the fine‐tuning of the general Ser/Thr pharmacophore to desired types of kinase to get active and selective inhibitors was exemplified by Aurora A kinase. As a result, several hits in 3–5 nm range of activity against Aurora A kinase with rather good selectivity and ADME properties were obtained.