Decision-making factors for the long-term topical treatment of mild-to-moderate plaque psoriasis: TEPPSO, a case-vignette study on clinical practice.

OBJECTIVES: Topical maintenance therapy strategy with regard to patients with mild-to-moderate plaque psoriasis (PP) continues to be heterogeneous and insufficiently investigated in real-life clinical practice. The objective of this study was to describe the initiation of long-term maintenance treatment and to identify clinical parameters influencing the therapeutic decision. METHODS: TEPPSO was a French and Belgian multicentre cross-sectional study based on completion of questionnaires and assessment of credible clinical scenarios of mild-to-moderate PP by physicians using the validated case-vignette method. RESULTS: Maintenance therapy was recommended by dermatologists (Ds) and by general practitioners (GPs) in 79.1% and 76.8% of cases, respectively. GPs recommended the use of a fixed-dose combination of corticosteroid and vitamin D analogues in only 14.8% of cases, whereas this therapy was recommended by French and Belgian Ds in 54.8% and 39.8% of cases, respectively. In a multivariate analysis, significant determinants of the therapeutic decision were skin lesions impacting quality of life (OR 1.9 [95% CI: 1.1; 3.2] P=0.01) for Ds, and patient corticophobia (OR 1.7 [95% CI: 1.1; 2.7] P=0.03) or the presence of skin pruritus (OR 1.8 [95% CI: 1.2; 1.8] P=0.004) for GPs, respectively. CONCLUSIONS: Maintenance treatment with topical agents in patients with mild-to-moderate PP was considered in more than two thirds of cases. Heterogeneity in the choice of topical agents was evidenced particularly between Ds and GPs. Our study is the first to identify significant clinical determinants affecting the therapeutic decision. Updated and validated clinical practice guidelines are needed to ensure uniform therapeutic choices.

Peripheral venous catheter colonization after skin disinfection with 0.5% aqueous sodium hypochlorite, preceded or not by one application of 70% ethanol (DACLEAN): a single-centre, randomized, open-label, pilot study.

Few data are available on the efficacy of 0.5% aqueous sodium hypochlorite (SH) for skin disinfection before peripheral catheter insertion. A total of 239 patients were randomly assigned to either one application of SH alone or one application of SH preceded by one application of 70% ethanol (ET-SH). Catheter colonization, defined as a catheter tip culture growing >1000 cfu of a micro-organism per millilitre, occurred in 29 patients (33% of 89 colonizations per 1000 catheter-days) in the SH group and in 31 patients (33% of 126 colonizations per 1000 catheter-days) in the ET-SH group.

Evaluation of the Ryegrass Stem Rust Model STEMRUST_G and Its Implementation as a Decision Aid.

STEMRUST_G, a simulation model for epidemics of stem rust in perennial ryegrass grown to maturity as a seed crop, was validated for use as a heuristic tool and as a decision aid for disease management with fungicides. Multistage validation had been used in model creation by incorporating previously validated submodels for infection, latent period duration, sporulation, fungicide effects, and plant growth. Validation of the complete model was by comparison of model output with observed disease severities in 35 epidemics at nine location-years in the Pacific Northwest of the United States. We judge the model acceptable for its purposes, based on several tests. Graphs of modeled disease progress were generally congruent with plotted disease severity observations. There was negligible average bias in the 570 modeled-versus-observed comparisons across all data, although there was large variance in size of the deviances. Modeled severities were accurate in >80% of the comparisons, where accuracy is defined as the modeled value being within twice the 95% confidence interval of the observed value, within ±1 day of the observation date. An interactive website was created to produce disease estimates by running STEMRUST_G with user-supplied disease scouting information and automated daily weather data inputs from field sites. The model and decision aid supplement disease managers' information by estimating the level of latent (invisible) and expressed disease since the last scouting observation, given season-long weather conditions up to the present, and it estimates effects of fungicides on epidemic development. In additional large-plot experiments conducted in grower fields, the decision aid produced disease management outcomes (management cost and seed yield) as good as or better than the growers' standard practice. In future, STEMRUST_G could be modified to create similar models and decision aids for stem rust of wheat and barley, after additional experiments to determine appropriate parameters for the disease in these small-grain hosts.

Inhibition of autophagy, lysosome and VCP function impairs stress granule assembly.

Stress granules (SGs) are mRNA-protein aggregates induced during stress, which accumulate in many neurodegenerative diseases. Previously, the autophagy-lysosome pathway and valosin-containing protein (VCP), key players of the protein quality control (PQC), were shown to regulate SG degradation. This is consistent with the idea that PQC may survey and/or assist SG dynamics. However, despite these observations, it is currently unknown whether the PQC actively participates in SG assembly. Here, we describe that inhibition of autophagy, lysosomes and VCP causes defective SG formation after induction. Silencing the VCP co-factors UFD1L and PLAA, which degrade defective ribosomal products (DRIPs) and 60S ribosomes, also impaired SG assembly. Intriguingly, DRIPs and 60S, which are released from disassembling polysomes and are normally excluded from SGs, were significantly retained within SGs in cells with impaired autophagy, lysosome or VCP function. Our results suggest that deregulated autophagy, lysosomal or VCP activities, which occur in several neurodegenerative (VCP-associated) diseases, may alter SG morphology and composition.

Immunosuppressant regimen based on sirolimus decreases aortic stiffness in renal transplant recipients in comparison to cyclosporine.

Whether or not a cyclosporine A (CsA)-free immunosuppressant regimen based on sirolimus (SRL) prevents aortic stiffening and improves central hemodynamics in renal recipients remains unknown. Forty-four patients (48 ± 2 years) enrolled in the CONCEPT trial were randomized at week 12 (W12) to continue CsA or switch to SRL, both associated with mycophenolate mofetil. Carotid systolic blood pressure (cSBP), pulse pressure (cPP), central pressure wave reflection (augmentation index, AIx) and carotid-to-femoral pulse-wave velocity (PWV: aortic stiffness) were blindly assessed at W12, W26 and W52 together with plasma endothelin-1 (ET-1), thiobarbituric acid-reactive substances (TBARS) and superoxide dismutase (SOD) and catalase erythrocyte activities. At W12, there was no difference between groups. At follow-up, PWV, cSBP, cPP and AIx were lower in the SRL group. The difference in PWV remained significant after adjustment for blood pressure and eGFR. In parallel, ET-1 decreased in the SRL group, while TBARS, SOD and catalase erythrocyte activities increased in both groups but to a lesser extent in the SRL group. Our results demonstrate that a CsA-free regimen based on SRL reduces aortic stiffness, plasma endothelin-1 and oxidative stress in renal recipients suggesting a protective effect on the arterial wall that may be translated into cardiovascular risk reduction.

Long-term impact of subclinical inflammation diagnosed by protocol biopsy one year after renal transplantation.

The long-term impact of subclinical acute rejection (SCAR) on renal graft function remains poorly understood. Furthermore, the interpretation of borderline lesions is difficult and their incidence is variable. The aim of this study was to analyze the characteristics of subclinical inflammation (SCI) in protocol biopsies performed 1-year after renal transplantation. SCI was defined as the presence of borderline lesions or SCAR according to the Banff 2005 classification. The patients included were a subpopulation of the CONCEPT study in which patients were randomized 3 months after transplantation to receive either sirolimus (SRL) or cyclosporine A (CsA) in combination with mycophenolate mofetil. At 1 year, we observed SCI in 37 of the 121 patients observed with an evaluable biopsy. The incidence was more frequent in the SRL group (SRL 45.2% vs. CsA 15.3%). At 30 months , SCI was associated with a significantly lower level of estimated glomerular filtration rate (mean MDRD 50.8 [±13.3] vs. 57.7 [±16.3] mL/min/1.73 m(2) , p = 0.035). In conclusion, SCI at 1-year posttransplantation is associated with worsening renal function and is more frequent in SRL-treated patients. Therefore, evaluation of SCI may be a valuable tool to allow the optimization of immunosuppressive regimens.

Efficacy and safety of early cyclosporine conversion to sirolimus with continued MMF-four-year results of the Postconcept study.

Calcineurin inhibitor (CNI) withdrawal has been used as a strategy to improve renal allograft function. We previously reported that conversion from cyclosporine A (CsA) to sirolimus (SRL) 3 months after transplantation significantly improved renal function at 1 year. In the Postconcept trial, 77 patients in the SRL group and 85 in the CsA group were followed for 48 months. Renal function (Cockcroft and Gault) was significantly better at month 48 (M48) in the SRL group both in the intent-to-treat population (ITT): 62.6 mL/min/1.73 m(2) versus 57.1 mL/min/1.73 m(2) (p = 0.013) and in the on-treatment population (OT): 67.5 mL/min/1.73 m(2) versus 57.4 mL/min/1.73 m(2) (p = 0.002). Two biopsy proven acute rejection episodes occurred after M12 in each group. Graft and patient survival were comparable (graft survival: 97.4 vs. 100%; patient survival: 97.4 vs. 97.6%, respectively). The incidence of new-onset diabetes was numerically increased in the SRL group (7 vs. 2). In OT, three cancers occurred in the SRL group versus nine in the CsA group and mean proteinuria was increased in the SRL group (0.42 ± 0.44 vs. 0.26 ± 0.37; p = 0.018). In summary, the renal benefits associated with conversion of CsA to SRL, at 3 months posttransplantation, in combination with MMF were maintained for 4 years posttransplantation.

Long-Term Impact of Cyclosporin Reduction with MMF Treatment in Chronic Allograft Dysfunction: REFERENECE Study 3-Year Follow Up.

Calcineurin inhibitor (CNI) toxicity contributes to chronic allograft nephropathy (CAN). In the 2-year, randomized, study, we showed that 50% cyclosporin (CsA) reduction in combination with mycophenolate mofetil (MMF) treatment improves kidney function without increasing the risk for graft rejection/loss. To investigate the long-term effect of this regimen, we conducted a follow up study in 70 kidney transplant patients until 5 years after REFERENCE initiation. The improvement of kidney function was confirmed in the MMF group but not in the control group (CsA group). Four graft losses occurred, 2 in each group (graft survival in the MMF group 95.8% and 90.9% in control group). One death occurred in the control group. There was no statistically significant difference in the occurrence of serious adverse events or acute graft rejections. A limitation is the weak proportion of patient still remaining within the control group. On the other hand, REFERENCE focuses on the CsA regimen while opinions about the tacrolimus ones are still debated. In conclusion, CsA reduction in the presence of MMF treatment seems to maintain kidney function and is well tolerated in the long term.

High expression of gabarapl1 is associated with a better outcome for patients with lymph node-positive breast cancer.

BACKGROUND: This study evaluates the relation of the early oestrogen-regulated gene gabarapl1 to cellular growth and its prognostic significance in breast adenocarcinoma. METHODS: First, the relation between GABARAPL1 expression and MCF-7 growth rate was analysed. Thereafter, by performing macroarray and reverse transcriptase quantitative-polymerase chain reaction (RT-qPCR) experiments, gabarapl1 expression was quantified in several histological breast tumour types and in a retrospective cohort of 265 breast cancers. RESULTS: GABARAPL1 overexpression inhibited MCF-7 growth rate and gabarapl1 expression was downregulated in breast tumours. Gabarapl1 mRNA levels were found to be significantly lower in tumours presenting a high histological grade, with a lymph node-positive (pN+) and oestrogen and/or progesterone receptor-negative status. In univariate analysis, high gabarapl1 levels were associated with a lower risk of metastasis in all patients (hazard ratio (HR) 4.96), as well as in pN+ patients (HR 14.96). In multivariate analysis, gabarapl1 expression remained significant in all patients (HR 3.63), as well as in pN+ patients (HR 5.65). In univariate or multivariate analysis, gabarapl1 expression did not disclose any difference in metastasis risk in lymph node-negative patients. CONCLUSIONS: Our data show for the first time that the level of gabarapl1 mRNA expression in breast tumours is a good indicator of the risk of recurrence, specifically in pN+ patients.

Efficacy on renal function of early conversion from cyclosporine to sirolimus 3 months after renal transplantation: concept study.

Sirolimus (SRL) allows to minimize the use of cyclosporine (CsA), but de novo administration after transplantation is associated with various complications. We report a prospective, open-label, multicenter randomized study to evaluate conversion from a CsA-based regimen to a SRL-based regimen 3 months after transplantation. One hundred ninety-two of a total of 237 patients were eligible at 3 months to be converted to SRL (n = 95) or to continue CsA (n = 97). All patients were also given mycophenolate mofetil (MMF) and oral steroids, planned to be discontinued at month 8. The primary endpoint, the clearance estimated according to Cockcroft and Gault at week 52, was significantly better in the SRL group (68.9 vs. 64.4 mL/min, p = 0.017). Patient and graft survival were not statistically different. The incidence of acute rejection episodes, mainly occurring after withdrawal of steroids, was numerically but not statistically higher in the SRL group (17% vs. 8%, p = 0.071). Sixteen patients discontinued SRL, mainly for adverse events (n = 11), and seven patients discontinued CsA for renal failure or acute rejection. Significantly, more patients in the SRL group reported aphthous, diarrhea, acne and high triglyceride levels. Conversion CsA to SRL 3 months after transplantation combined with MMF is associated with improvement in renal function.

Impact of cyclosporine reduction with MMF: a randomized trial in chronic allograft dysfunction. The 'reference' study.

Long-term use of calcineurine inhibitors (CNIs) may contribute to the development of chronic allograft dysfunction (CAD). We investigate the impact of the introduction of MMF combined with cyclosporine (CsA) 50% dose reduction. An open, randomized, controlled, multicenter, prospective study was conducted in 103 patients, receiving a CsA-based therapy with a serum creatinine between 1.7-3.4 mg/dL, more than 1 year after transplantation. They were randomized to receive MMF with half dose of CsA (MMF group) or to continue their maintenance CsA dose (control group). A total of 96 weeks after randomization, the evolution of renal function assessed by regression line analysis of 1/SeCr improved in the MMF group (positive slope) vs. the control group (negative slope), 4.2 x 10(-4) vs. -3.0 x 10(-4), respectively (p < 0.001). Concurrently, the absolute renal function improved significantly in the MMF group. No episode of biopsy-proven acute rejection occurred. One patient in each group lost his graft because of biopsy-proven chronic allograft nephropathy. There was a significant decrease of triglycerides level in the MMF group. Anemia and diarrhea were statistically more frequent in the MMF group. In CAD, the reduction of CsA in the presence of MMF results in significant improvement in renal function during a 2-year follow-up.

Dermatomyositis and malignant melanoma.

Patients with dermatomyositis may face an increased risk of malignancy. Malignant melanoma has been linked to dermatomyositis. We present a case of concomitant dermatoyositis and metastatic malignant melanoma and review the English literature concerning this topic. Analysis revealed that the development of dermatomyositis in patients with malignant melanoma heralds the diagnosis of metastatic disease. These patients face dismal prognoses.

Sleep permissive components within the dorsal raphe nucleus in the rat.

Two peptides known for their hypnogenic properties, CLIP (corticotropin-like intermediate lobe peptide or ACTH 18-39) or VIP (vasoactive intestinal polypeptide), were injected locally into the nucleus raphe dorsalis (nRD) of rats pretreated with p-chlorophenylalanine (PCPA). During the dark period, the PCPA insomnia was primarily associated with a reduction in paradoxical sleep (PS), whereas both slow wave sleep (SWS) and PS were decreased during the light period. Immunohistochemistry of serotonin in PCPA-pretreated animals indicated a clear disappearance of 5-HT fibers in the basal hypothalamus and the nRD as compared to control animals. Local injections of CLIP or VIP in the nRD restored PS and SWS. The positive injection sites corresponded to the anatomical distribution of either CLIP or VIP fibers, i.e., the entire nRD for VIP and the antero-dorsal part of this nucleus for CLIP. The sleep effects obtained in PCPA-pretreated rats involve a non-5-HT sleep permissive component within the nRD upon which these injected peptides act.

Cardiovascular effects of pseudoephedrine in medically controlled hypertensive patients.

BACKGROUND: Oral sympathomimetics are effective in the treatment of nasal congestion through stimulation of alpha-adrenergic receptors in the blood vessels of the nasal mucosa. This vasoconstrictor activity has resulted in the general recommendation that such pressor amines not be used in patients with hypertension. No prospective studies have examined the safety of sustained-release pseudoephedrine in hypertensive patients. METHODS: Volunteers (N = 28) with controlled hypertension participated in a randomized, double-blind, placebo-controlled, crossover study that examined the cardiovascular effects of 120 mg of sustained-release pseudoephedrine taken on a twice daily basis. Physician-investigators measured blood pressure and heart rate using mercurial sphygmomanometers during acute and steady-state phases. Compliance was verified with pill counts and serum drug levels. Symptom questionnaires were completed by the volunteers. RESULTS: While a strong statistical correlation was found over time, with minimal increases in mean arterial pressure and heart rate, pseudoephedrine administration did not result in statistically significant changes in any cardiovascular parameter. Mild disturbances in sleeping pattern and urinary retention in some male subjects were the only significant symptoms detected. CONCLUSIONS: We conclude that while sustained-release pseudoephedrine appears safe for the majority of medically controlled hypertensive patients without statistically significant effects on blood pressure or heart rate our studies did show an upward trend in these parameters which, in a larger population of hypertensive patients, may prove to be clinically significant.

[Systemic or intracerebral injection of bovine neurointermediate lobe extracts may induce paradoxical sleep in insomnia induced by p-chlorophenylalanine in cats]. / L'injection systémique ou intracérébrale d'extraits de lobe neuro-intermédiaire de Boeuf peut induire le sommeil paradoxal au cours de l'insomnie provoquée par la P. chlorophénylalanine chez le chat.

Injections of Bovine neuro-intermediate lobe extracts, either subcutaneously (5 U), intraventricularly (20 mU) or directly in the vicinity of the nucleus magnocellularis of the medulla (1,3 mU) may induce paradoxical sleep in totally insomniac cats pretreated with P. chlorophenylalanine.

Elongation of the First Internode of the Pea Seedling during Etiolation : Interaction of Environment and Genotype.

In the present study, 40 lines of peas, Pisum sativum L., from the Weibullsholm collection were examined for elongation response of the first internode to growth in soil, sand, or in darkness in air. The results obtained establish that appearance of the first (lowest) node of the epicotyl at the surface of soil was usual in only a few of the lines tested (L25, L1088, L1570). By contrast, appearance of the first node at the surface of sand as a result of enhancement of first internode extension occurred in 80% of the lines tested. In many lines, extension in sand or soil was more than in darkness in air, a surprising observation given that the known response of the pea epicotyl to pressure is to produce the extension inhibitor, ethylene. Results of two crosses, one of tallxdwarf and one of tallxtall, point to the conclusion that the Le/le locus exercises only partial control over first internode extension and that other, as yet unknown, loci are implicated.

Local cerebral glucose utilization during waking and slow wave sleep in the cat. A [14C]deoxyglucose study.

Local cerebral glucose utilization (LCGU) was measured during spontaneous waking and slow wave sleep (SWS) by an adaptation of the [14C]deoxyglucose method to the free moving cat. In awake animals heterogeneous rates of LCGU were observed throughout the brain with values extending from 8 mumol x 100 g-1 x min-1 for white matter, to 113 for the inferior colliculus. There was no significant difference for LCGU in SWS compared with awake animals.

Glucose utilization increases in choroid plexus during slow wave sleep. A [14C] deoxyglucose study in the cat.

Glucose utilization (GU) was measured during spontaneous waking and slow-wave sleep (SWS) by adaptation of the [14C]deoxyglucose method to the unrestrained cat. In sleeping animals a greater autoradiographic signal between choroid plexus (CP) and the rest of brain was noticed. Quantification provided an index of the metabolic rate of CP and confirmed that mean values for GU were significantly higher in "sleeping' than in "awake' cats.