Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety

Background and purpose:

Thrombus formation is commonly associated with pulmonary arterial hypertension (PAH). Thrombin may thus play an important role in the pathogenesis and pathophysiology of PAH. Hence, we investigated the contractile effects of thrombin and its mechanism in pulmonary artery.

Experimental approach:

The cytosolic Ca²⁺ concentrations ([Ca²⁺]_i), 20 kDa myosin light chain (MLC20) phosphorylation and tension development were evaluated using the isolated porcine pulmonary artery.

Key results:

Thrombin induced a sustained contraction in endothelium-denuded strips obtained from different sites of a pulmonary artery, ranging from the main pulmonary artery to the intrapulmonary artery. In the presence of endothelium, thrombin induced a transient relaxation. The contractile effect of thrombin was abolished by either a protease inhibitor or a proteinase-activated receptor 1 (PAR₁) antagonist, while it was mimicked by PAR₁-activating peptide (PAR₁AP), but not PAR₄AP. The thrombin-induced contraction was associated with a small elevation of [Ca²⁺]_i and an increase in MLC20 phosphorylation. Thrombin and PAR₁AP induced a greater increase in tension for a given [Ca²⁺]_i elevation than that obtained with high K⁺-depolarization. They also induced a contraction at a fixed Ca²⁺ concentration in α-toxin-permeabilized preparations.

Conclusions and implications:

The present study revealed a unique property of the pulmonary artery. In contrast to normal arteries of the systemic circulation, thrombin induces a sustained contraction in the normal pulmonary artery, by activating PAR₁ and thereby increasing the sensitivity of the myofilament to Ca²⁺. This responsiveness of the pulmonary artery to thrombin may therefore contribute to the pathogenesis and pathophysiology of PAH.     

Multimodal imaging of the macula in hereditary and acquired lack of macular pigment

Purpose: Macular pigment (MP) deficit has been described in macular teleangiectasia type 2 (MTA; acquired MP loss) and in Sjögren–Larsson syndrome (SLS; hereditary MP deficiency). Central blue light‐induced fundus autofluorescence (FAF) and blue light fundus reflectance (BLR) are thought to reflect MP distribution. This study was performed to describe the macular morphology in SLS and MTA by multimodal imaging to further investigate the causes of FAF and BLR changes in these disorders. Methods: This was a single‐centre, cross‐sectional, retrospective, observational study on SLS and MTA patients treated at our institution. In a multimodal retinal imaging dataset, patterns of BLR and FAF changes were compared with the optical coherence tomography (OCT) and clinical appearance of the patients’ retinas. Results: Multimodal image sets of seven eyes of four patients with SLS and of 25 eyes of 15 patients with MTA were included in this study. In MTA, areas of focal FAF increase were mainly associated with retinal pseudocysts and photoreceptor loss and were co‐located with regions of increased BLR. In SLS, areas of focally decreased FAF correlated with the typical intraretinal glistening dots. Frequently, a spot of focally increased FAF was visible at the fovea of SLS patients, often independent of the presence of pseudocysts or photoreceptor loss on OCT. Conclusion: In MTA and SLS different patterns of FAF alterations could be observed. The areas of increased BLR, which are thought to correlate with MP loss, appeared to have only restricted correlation with FAF appearance.     

Ophthalmic epidemiology in Europe: the “European Eye Epidemiology” (E3) consortium

The European Eye Epidemiology (E3) consortium is a recently formed consortium of 29 groups from 12 European countries. It already comprises 21 population-based studies and 20 other studies (case–control, cases only, randomized trials), providing ophthalmological data on approximately 170,000 European participants. The aim of the consortium is to promote and sustain collaboration and sharing of data and knowledge in the field of ophthalmic epidemiology in Europe, with particular focus on the harmonization of methods for future research, estimation and projection of frequency and impact of visual outcomes in European populations (including temporal trends and European subregions), identification of risk factors and pathways for eye diseases (lifestyle, vascular and metabolic factors, genetics, epigenetics and biomarkers) and development and validation of prediction models for eye diseases. Coordinating these existing data will allow a detailed study of the risk factors and consequences of eye diseases and visual impairment, including study of international geographical variation which is not possible in individual studies. It is expected that collaborative work on these existing data will provide additional knowledge, despite the fact that the risk factors and the methods for collecting them differ somewhat among the participating studies. Most studies also include biobanks of various biological samples, which will enable identification of biomarkers to detect and predict occurrence and progression of eye diseases. This article outlines the rationale of the consortium, its design and presents a summary of the methodology.     

Survival of a 30-week baby with congenital myotonic dystrophy initially ventilated for 55 days

In previous reports, duration of initial ventilation exceeding 1 month almost always predicts non-survival of babies with congenital myotonic dystrophy. However, a baby with this condition survived beyond infancy after 55 days' ventilation. We describe this case in detail, explain why the baby survived and highlight the importance of individualized assessment, in addition to applying general prognostic terms described in the literature.     

Large deletions of the KCNV2 gene are common in patients with cone dystrophy with supernormal rod response

Cone dystrophy with supernormal rod response (CDSRR) is considered to be a very rare autosomal recessive retinal disorder. CDSRR is associated with mutations in KCNV2, a gene that encodes a modulatory subunit (Kv8.2) of a voltage-gated potassium channel. In this study, we found that KCNV2 mutations are present in a substantial fraction (2.2-4.3%) of a sample of 367 independent patients with a variety of initial clinical diagnoses of cone malfunction, indicating that CDSRR is underdiagnosed and more common than previously thought. In total, we identified 20 different KCNV2 mutations; 15 of them are novel. A new finding of this study is the substantial proportion of large deletions at the KCNV2 locus that accounts for 15.5% of the mutant alleles in our sample. We determined the breakpoints and size of all five different deletions, which ranged between 10.9 and 236.8 kb. Two deletions encompass the entire KCNV2 gene and one also includes the adjacent VLDLR gene. Furthermore, we investigated N-terminal amino acid substitution mutations for its effect on interaction with Kv2.1 using yeast two-hybrid technology. We found that these mutations dramatically reduce or abolish this interaction suggesting a lack of assembly of heteromeric Kv channels as one underlying pathomechanism of CDSRR.     

Erg?nzung und Unterstützung zu konventionellen Tumortherapien Misteltherapie

Die anthroposophische Misteltherapie kann etablierte onkologische Standardtherapien im Sinne einer umfassenderen und ganzheitlichen Versorgung erg?nzen.