Effects of mycophenolate mofetil on key pattern of coronary restenosis: a cascade of in vitro and ex vivo models

BACKGROUND: Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is a rationally designed immunosuppressive drug. The current study investigates the effect of MMF on key pattern of restenosis in a cascade of in vitro and ex vivo models. METHODS: Part I of the study investigated in northern blot and cytoflow studies the effect of MMF (50, 100, 150, 200, 250, and 300 μg/mL) on TNF-α induced expression of intercellular adhesion molecule 1 (ICAM-1) in human coronary endothelial cells (HCAEC) and human coronary medial smooth muscle cells (HCMSMC). Part II of the study applied a human coronary 3D model of leukocyte attack, the 3DLA-model. HCAEC and HCMSMC were cultured on both sides of a polycarbonate filters, mimicking the internal elastic membrane. Leukocyte attack (LA) was carried out by adding human monocytes (MC) on the endothelial side. The effect of MMF (50 μg/mL) on adhesion and chemotaxis (0.5, 1, 2, 3, 4, 6, and 24 h after LA) and the effect on proliferation of co-cultured HCMSMC (24 h after LA) was studied. In part III of the study a porcine coronary organ culture model of restenosis (POC-model) was used. After ex vivo ballooning MMF (50 μg/mL) was added to the cultures for a period of 1, 2, 3, 4, 5, 6, and 7 days. The effect on reactive cell proliferation and neointimal thickening was studied at day 7 and day 28 after ballooning. RESULTS: Expression of ICAM-1 in northern blot and cytoflow studies was neither clearly inhibited nor stimulated after administration of MMF in the clinical relevant concentration of 50 μg/mL. In the 3DLA-model 50 μg/mL of MMF caused a significant antiproliferative effect (p < 0.001) in co-cultured HCMSMC but had no effect on MC-adhesion and MC-chemotaxis. In the ex vivo POC-model neighter reactive cell proliferation at day 7 nor neointimal hyperplasia at day 28 were significantly inhibited by MMF (50 μg/mL). CONCLUSION: Thus, the data demonstrate a significant antiproliferative effect of clinical relevant levels of MMF (50 μg/mL) in the 3DLA-model. The antiproliferative effect was a direct antiproliferative effect that was not triggered via reduced expression of ICAM-1 or via an inhibition of MC-adhesion and chemotaxis. Probably due to technical limitations (as e.g. the missing of perfusion) the antiproliferative effect of MMF (50 μg/mL) could not be reproduced in the coronary organ culture model. A cascade of focused in vitro and ex vivo models may help to gather informations on drug effects before large experimental studies are initiated

Understanding national trends in COVID-19 vaccine hesitancy in Canada: results from five sequential cross-sectional representative surveys spanning April 2020–March 2021

Objective: To examine rates of vaccine hesitancy and their correlates among Canadian adults between April 2020 and March 2021. Design: Five sequential cross-sectional age, sex and province-weighted population-based samples who completed online surveys. Setting: Canada. Participants: A total of 15 019 Canadians aged 18 years and over were recruited through a recognised polling firm (Leger Opinion). Respondents were 51.5% female with a mean age of 48.1 (SD 17.2) years (range 18–95 years) and predominantly white (80.8%). Primary and secondary outcome measures: Rates of vaccine hesitancy over the five surveys (time points) and their sociodemographic, clinical and psychological correlates. Results: A total of 42.2% of respondents reported some degree of vaccine hesitancy, which was lowest during surveys 1 (April 2020) and 5 (March 2021) and highest during survey 3 (November 2020). Fully adjusted multivariate logistic regression analyses revealed that women, those aged 50 and younger, non-white, those with high school education or less, and those with annual household incomes below the poverty line in Canada were significantly more likely to report vaccine hesitancy, as were essential and healthcare workers, parents of children under the age of 18 and those who do not get regular influenza vaccines. Endorsing prevention behaviours as important for reducing virus transmission and high COVID-19 health concerns were associated with 77% and 54% reduction in vaccine hesitancy, respectively. Having high personal financial concerns was associated with 1.33 times increased odds of vaccine hesitancy. Conclusions: Results highlight the importance of targeting vaccine efforts to specific groups by emphasising the outsized health benefits compared with risks of vaccination. Future research should monitor changes in vaccine intentions and behaviour to better understand underlying factors

The effect of autonomy, training opportunities, age and salaries on job satisfaction in the South East Asian retail petroleum industry

South East Asian petroleum retailers are under considerable pressure to improve service quality by reducing turnover. An empirical methodology from this industry determined the extent to which job characteristics, training opportunities, age and salary influenced the level of job satisfaction, an indicator of turnover. Responses are reported on a random sample of 165 site employees (a 68% response rate) of a Singaporean retail petroleum firm. A restricted multivariate regression model of autonomy and training opportunities explained the majority (35.4%) of the variability of job satisfaction. Age did not moderate these relationships, except for employees >21 years of age, who reported enhanced job satisfaction with additional salary. Human Capital theory, Life Cycle theory and Job Enrichment theory are invoked and explored in the context of these findings in the South East Asian retail petroleum industry. In the South East Asian retail petroleum industry, jobs providing employees with the opportunity to undertake a variety of tasks that enhanced the experienced meaningfulness of work are likely to promote job satisfaction, reduce turnover and increase the quality of service

Cancer therapy and cardiotoxicity: The need of serial Doppler echocardiography

Cancer therapy has shown terrific progress leading to important reduction of morbidity and mortality of several kinds of cancer. The therapeutic management of oncologic patients includes combinations of drugs, radiation therapy and surgery. Many of these therapies produce adverse cardiovascular complications which may negatively affect both the quality of life and the prognosis. For several years the most common noninvasive method of monitoring cardiotoxicity has been represented by radionuclide ventriculography while other tests as effort EKG and stress myocardial perfusion imaging may detect ischemic complications, and 24-hour Holter monitoring unmask suspected arrhythmias. Also biomarkers such as troponine I and T and B-type natriuretic peptide may be useful for early detection of cardiotoxicity. Today, the widely used non-invasive method of monitoring cardiotoxicity of cancer therapy is, however, represented by Doppler-echocardiography which allows to identify the main forms of cardiac complications of cancer therapy: left ventricular (systolic and diastolic) dysfunction, valve heart disease, pericarditis and pericardial effusion, carotid artery lesions. Advanced ultrasound tools, as Integrated Backscatter and Tissue Doppler, but also simple ultrasound detection of "lung comet" on the anterior and lateral chest can be helpful for early, subclinical diagnosis of cardiac involvement. Serial Doppler echocardiographic evaluation has to be encouraged in the oncologic patients, before, during and even late after therapy completion. This is crucial when using anthracyclines, which have early but, most importantly, late, cumulative cardiac toxicity. The echocardiographic monitoring appears even indispensable after radiation therapy, whose detrimental effects may appear several years after the end of irradiation

Efficacy, safety and tolerability of an optimized avulsion technique with onyster\uae (40% urea ointment with plastic dressing) ointment compared to bifonazole-urea ointment for removal of the clinically infected nail in toenail onychomycosis: a randomized evaluator-blinded controlled study.

Background: Toenail onychomycosis is highly prevalent, with 14-28% of people aged 60 or over suffering from the disease. Use of a topical antifungal alone in toenail onychomycosis is associated with low cure rates. This may be due to limited penetration of the topical antifungal through the diseased nail. The objective of the present study was to compare two treatment modalities to obtain diseased nail chemical avulsion in toenail onychomycosis. Methods: In this European, multicenter, randomized, parallel-group, open-label, active-controlled study, male or female adult patients with distal-lateral or lateral subungual dermatophyte onychomycosis on at least 12.5% of the great toenail were randomized either to a 40% urea ointment with plastic dressing group (n = 53) or to a bifonazole-urea ointment group (n = 52). The ointments were applied daily for a maximum of 3 weeks according to the summary of product characteristics. After assessment of infected nail debridement, topical antifungal treatment with bifonazole cream was applied daily in both groups for 8 weeks. 102 patients were evaluated, i.e. 51 in the 40% urea ointment with plastic dressing group and 51 in the bifonazole-urea group. The primary end point was complete removal of the nail plate at day 21 (D21). Secondary end points were: complete cure and mycological cure evaluated at D105. Ease of use and local tolerability were also assessed. Results: Complete removal of the clinically infected target nail plate area, assessed by blinded evaluators, was significantly higher in the 40% urea ointment with plastic dressing group (61.2%) than in the control group (39.2%), showing the superiority of 40% urea ointment with plastic dressing (p = 0.028). The same results were observed in the per-protocol population (63.0 vs. 36.6%; p = 0.014). Complete removal of the infected area assessed by the investigator at D21 showed a significantly higher success rate in patients treated with 40% urea ointment with plastic dressing (86.3%) as compared to patients treated with bifonazole-urea (60.8%), confirming the superiority of 40% urea ointment with plastic dressing (p = 0.004). At D105, the complete cure of onychomycosis, a criterion combining clinical and mycological assessments, showed a success rate of 27.7% for 40% urea ointment with plastic dressing versus 20.8% for the control group. No statistical difference was observed between the two treatment groups. The number of patients with at least one adverse event was twice as high in the bifonazole-urea group in comparison to the 40% urea ointment with plastic dressing group. Overall assessment of local tolerability by the investigator was considered good/very good in 98.0% of the 40% urea ointment with plastic dressing patients versus 90.4% of the bifonazole-urea patients, at D21, with no significant difference between both groups. Conclusion: This study shows the superiority of 40% urea ointment with plastic dressing to bifonazole-urea ointment for complete removal of the infected target nail assessed by blinded evaluators and by the investigators. Further studies are needed to assess the impact of preliminary chemical nail avulsion on the efficacy of topical treatment of onychomycosis as assessed by complete cure at 1 year. \ua9 2013 S. Karger AG, Basel

HUVECs from newborns with a strong family history of myocardial infarction overexpress adhesion molecules and react abnormally to stimulating agents

Atherosclerosis is a complex disease involved in major fatal events such as myocardial infarction and stroke. It is the result of interactions between metabolic, dietetic and environmental risk factors acting on a genetic background that could result in endothelial susceptibility. Our aim was to determine the patterns of expression of adhesion molecules and whether phosphatidylserine is translocated to the cell surface of human umbilical vein endothelial cells (HUVECs) isolated from healthy newborns born to parents with a strong family history of myocardial infarction under TNF-α or oxLDL stimulated conditions. Compared to control HUVECs, experimental cords showed: (a) a four-fold increase in VCAM-1 expression under basal conditions, which showed no change after stimulation with the pro-atherogenic factors; (b) a two-fold increase in basal P-selectin expression that reached a 10-fold increase with any of the pro-atherogenic factors; (c) a basal ICAM-1 expression similar to P-selectin that was not modified by the pro-atherogenic molecules; (d) a similar PECAM-1 expression. Unexpectedly, phospathidylserine expression in experimental cord HUVECs was significantly increased (211 817 versus 3354 TFU) but was not associated to apoptotic death as the percentage of dead cells induced by TNF-α treatment was very low (0·55 versus 9·87% in control HUVECs). The latter result was corroborated by TUNEL staining. T cell adherence to HUVECs was highly up-regulated in the genetically predisposed samples. The analysis of nonpooled HUVECs, from newborns to family predisposed myocardial-infarction individuals, might represent a useful strategy to identify phenotypical and functional alterations, and hopefully, to take early preventive actions

Rhizobacteria with broad-spectrum antifungal activity

Antifungal rhizobacteria were obtained from maize, barley and chicory using direct or indirect isolation procedures. Effective isolates were tested for broad-spectrum activity against a set of phytopathogenic fungi. Isolates with broad-spectrum activity were identified as Pseudomonas fluorescens, P. cepacia, Serratia liquefaciens, S. plymuthica and Bacillus sp. Broad-spectrum compounds produced by P. cepacia and Erwinia herbicola were characterized as pyrrolnitrin and herbicolin-like compounds respectively