Quinacrine increases endothelial nitric oxide release: role of superoxide anion

The effect of acute quinacrine treatment on agonist-induced nitric oxide (NO) release was investigated in cultured human endothelial cells using electrochemical monitoring of the in situ NO concentration. Quinacrine dose-dependently increased NO release with an apparent EC50 of 0.2 microM and a maximal effect at 1 microM. Quinacrine did not modify the dependence of NO release on extracellular L-arginine. Acceleration or deceleration of O2- dismutation, which altered NO release in control cells, did not modify it in quinacrine-treated cells. Quinacrine did not modify NO amperometric signal or reaction with O2- produced by xanthine oxidation. In the presence of quinacrine, agonist-induced NO release became Mg2+ -independent and could not be attributed to an inhibition of phospholipase A2 activity. Quinacrine made NO release insensitive to Cu2+ chelation. The present study demonstrates that acute treatment by low quinacrine concentrations increases endothelial NO release, possibly through an inhibition of O2- production.     

Personality pathology and cognitive-behavioral treatment of fear of flying

Studies have been inconclusive about the influence of personality pathology on treatment outcome in anxiety disorders. In general, it has been presumed that treatment outcome is negatively influenced by the presence of personality pathology. This is a study of the prevalence of personality pathology among persons who were seeking help for fear of flying. Moreover, the effects of personality pathology on the results of a multimodal, standardized, cognitive-behavioral fear of flying treatment program employed by an agency that specializes in treating people with fear of flying were studied. Personality pathology was determined with a self-report questionnaire, which provides ICD-10 diagnoses of personality disorders and dimensional severity scores for personality pathology. Treatment outcome was assessed with three different fear of flying questionnaires. Based on clinical judgment after individual-case conceptualization, participants (N=922) were assigned to a particular treatment for fear of flying. Self-report data for fear of flying were collected at pretreatment and at 3, 6 and 12-month follow-ups in 659 participants who followed the 2-day treatment program. Moreover, the number of flights made in the year following treatment was determined.The results of this study showed that participants with personality pathology, mainly from cluster C (anxiety), report greater fear of flying before treatment than participants without personality pathology. After treatment fear of flying was significantly reduced. Presence of personality pathology was not predictive of the number of flights after treatment and scores on the VAFAS scale at short or long term. Only on two questionnaires for fear of flying collected at short-term participants with personality pathology obtained significantly higher scores, although the size of the differences was relatively small. It was concluded that participants with personality pathology also benefited from fear of flying treatment and that the presence of personality pathology although cannot be regarded as a contra indication for a standardized, cognitive-behavioral group treatment.     

Urticaria pigmentosa localized on radiation field

A woman previously treated by radiotherapy for a breast cancer developed urticaria pigmentosa mainly restricted to the irradiation field, without any systemic symptoms. Localized forms of urticaria pigmentosa are exceptional, and their triggering factors are poorly understood. Several hypotheses can be discussed in this peculiar observation, among which a direct role of radiotherapy in the occurrence of cutaneous lesions cannot be ruled out.     

Hepatitis C virus proteins do not directly trigger fibrogenic events in cultured human liver myofibroblasts

Summary. Although liver fibrosis is the major complication of hepatitis C virus (HCV) infection, the mechanisms of fibrogenesis in this setting are not completely understood. The aim of this study was to test the direct effect of HCV proteins on signalling- and fibrosis-related events in cultured human liver myofibroblasts, the effector cells of liver fibrogenesis. Cultured myofibroblasts were exposed to recombinant HCV core, a structural protein, and nonstructural proteins (NS) 3, NS 4 and NS 5. HCV proteins did not significantly increase DNA synthesis in myofibroblasts. We then examined if these proteins affected early signalling events. None of the HCV proteins affected the phosphorylation of the mitogen activated protein kinases/extracellular regulated kinases 1 and 2, or of the phosphatidylinositol 3-kinase target, Akt. HCV proteins had also no effect on intracellular calcium concentration. In other experiments, fibrogenesis-related parameters were measured. None of the HCV proteins had any effect on the secretion of type I collagen, tissue inhibitor of matrix metalloproteinases type 1, gelatinase or urokinase. Alpha-smooth muscle actin expression was also not modified. In summary, our experiments do not support a direct effect of these HCV proteins on fibrogenic cells.     

How does the Hospital and Anxiety and Depression Scale measure anxiety and depression in healthy subjects?

Many anxiety and depression scales are commonly used, although the assumption that they all measure the same construct may be questioned. Thus, researchers have to pay attention to the nature of the scales they use. The Hospital Anxiety and Depression Scale (HADS) was constructed in 1983 to allow a rapid and separate measure of depression and generalised anxiety. Surprisingly, since its introduction, there has been no comprehensive documentation of its psychometric properties. Therefore, as a contribution to assessing the construct validity of the HADS, we conducted a set of confirmatory factor analyses in a sample of 195 healthy students. None of the formerly proposed models fit our data. We were able to split the original Anxiety subscale into two components that we have labelled 'Anxiety' and 'Restlessness', while the original Depression subscale is slightly modified. The results are discussed from both clinical and theoretical points of view.     

Instrumental activation of bid by caspase-1 in a transgenic mouse model of ALS

Transgenic expression of mutant superoxide dismutase-1 (SOD1) produces an animal model of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. We have previously shown that the mitochondrial-dependent programmed cell death (PCD) pathway, including the redistribution of Bax, the cytosolic release of cytochrome c, and the activation of caspase-9, is recruited during neurodegeneration in spinal cords of transgenic mutant SOD1 mice. Herein, we show that the pro-PCD protein Bid is highly expressed in spinal cords of both wild-type and transgenic mutant SOD1 mice. While full-length Bid is found in the spinal cord of the two groups of mice, its cleaved form is only seen in transgenic mutant SOD1 mice, as early as the beginning of symptoms. In contrast, activated caspase-8, which is known to cleave Bid, is detected only at the end-stage of the disease. We also found that the expression of a dominant negative mutant of caspase-1 attenuates Bid cleavage as well as the mitochondrial release of cytochrome c, and the ensuing activation of caspase-9 and -3 in spinal cords of transgenic mutant SOD1 mice. These findings suggest that Bid cleavage may occur in this model by a pathway other than caspase-8 and shed light onto the molecular correlates of the previously reported beneficial effect of caspase-1 inhibition in transgenic mutant SOD1 mice.     

Synthesis and DNA interaction of a mixed proflavine-phenanthroline Tröger base

We report the synthesis of an asymmetric Tr?ger base containing the two well characterised DNA binding chromophores, proflavine and phenanthroline. The mode of interaction of the hybrid molecule was investigated by circular and linear dichroism experiments and a biochemical assay using DNA topoisomerase I. The data are compatible with a model in which the proflavine moiety intercalates between DNA base pairs and the phenanthroline ring occupies the DNA groove. DNase I cleavage experiments were carried out to investigate the sequence preference of the hybrid ligand and a well resolved footprint was detected at a site encompassing two adjacent 5'-GTC.5-GAC triplets. The sequence preference of the asymmetric molecule is compared to that of the symmetric analogues.     

Determinants of discontinuation of new courses of antihypertensive medications

Discontinuation of medication use constitutes a major barrier to adequate control of high blood pressure. We examined the effect of an array of potential predisposing, enabling and reinforcing factors on the discontinuation of newly prescribed antihypertensive medications. We conducted a prospective cohort study through a network of 173 pharmacies across Canada where were identified individuals newly prescribed an antihypertensive monotherapy. We interviewed participants by telephone four times to obtain information for a minimum duration of 18 months after entry into the cohort. We analyzed data using a multivariate proportional hazard model. Of 682 eligible participants, 43.3% had discontinued their initial medication at the end of the observation period. Individuals more likely to discontinue their initial medication were those who perceived side effects from this medication [Hazard Ratio (HR) = 1.91; 95% Confidence Interval (CI) 1.47-2.47). Individuals with medication insurance coverage were less likely to discontinue (HR = 0.74; 95% CI 0.55-0.99). Persistence with newly prescribed medications could be improved by selecting antihypertensive medications containing fewer side effects and by lifting economic barriers to drug treatment.     

Oxygène, stress oxydant et supplémentations antioxydantes ou un aspect différent de la nutrition dans les maladies respiratoires

Dioxygen is an element essential to our survival, our life, our development, our capacity of adaptation. Nevertheless, dioxygen is also at the origin of toxicity, acidity, deterioration, degeneration. Indeed, when the metabolism of dioxygen is altered, as in the respiratory diseases, an “oxidative stress” can appeared and induced metabolic anomalies associated with important consequences. Oxidative stress is defined as an imbalance between pro-oxidant (reactive oxygen species) and antioxidant factors, in favour of the former. The genomic, metabolic and functional modifications induced by oxidative stress were implied in the development of various degenerative diseases. Antioxidant treatments, in a nutritional or pharmacological way, appeared consequently as new potent therapies. In this review, the role of dioxygen in the cellular metabolism, and in the production of the reactive oxygen species is discussed. The negative effects of the oxidative stress on the organism are reported. Finally, the results of the studies on the nutritional antioxidant treatment firstly in the degenerative diseases, secondly in a chronic respiratory disease, the chronic obstructive pulmonary disease, are discussed in a last part.