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.     

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.     

Anthropomorphic radiologic phantoms

A technique is being developed for the design and fabrication of anthropomorphic phantoms for diagnostic x-ray imaging. Anatomic information extracted from actual patient radiographs is incorporated into the phantoms using computer image processing and computer-assisted machining methods. In this paper, the technique is described as applied to a breast phantom, and preliminary images that closely mimic human anatomy on radiographs are shown.     

Erg?nzung und Unterstützung zu konventionellen Tumortherapien Misteltherapie

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

Contact sensitizers downregulate the expression of the chemokine receptors CCR6 and CXCR4 in a skin dendritic cell line

Chemokines are involved in the control of dendritic cell (DC) trafficking, which is critical for the immune response, namely in allergic contact dermatitis (ACD). In this work, we investigated by flow cytometry the effect of the contact sensitizers 2,4-dinitrofluorobenzene (DNFB), 1,4-phenylenediamine (PPD) and nickel sulfate (NiSO₄), on the surface expression of the chemokine receptors CCR6 and CXCR4 in DC. As an experimental model of a DC we used a fetal skin-derived dendritic cell line (FSDC), which has morphological, phenotypical and functional characteristics of skin DC. Our results show that all the skin sensitizers studied decreased the membrane expression of the chemokine receptors CCR6 and CXCR4. In contrast, 2,4-dichloronitrobenzene (DCNB), the inactive analogue of DNFB without contact sensitizing properties, was without effect on the surface expression of these receptors. Lipopolysaccharide (LPS), which induces the maturation of DC, also reduced surface CCR6 and CXCR4 expression.     

Neuro-ophthalmological manifestations of systemic lupus erythematosus in Asian patients

Purpose : To report eight patients with diagnosed systemic lupus erythematosus (SLE) who presented with a variety of neuro‐ophthalmological complications and outcomes. Methods : A review of the follow up, subsequent management and outcomes of the neuro‐ophthalmological complications of eight patients with SLE. Results : The patients presented with a myriad of symptoms of varying severities. The most common manifestations were that of optic neuropathy and eye movement abnormalities. The outcome was variable ranging from complete recovery to optic atrophy with navigational visual acuity. Treatment was often empirical, although early treatment with corticosteroids has been tried with varying success. Conclusions : The pathophysiology in the neuro‐ ophthalmological manifestations of SLE is thought be due to vaso‐occlusive disease of the small vessels of the nerve and brain, secondary to an autoimmune process. Ophthalmologists may need to consider the diagnosis of SLE in young women who present with a recent onset of neuro‐ophthalmological symptoms and signs.