Meta-analysis of epigenome-wide association studies of carotid intima-media thickness

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta?=??0.0264, p value?=?3.5?×?10^–8) in the discovery panel and was replicated in replication panel (beta?=??0.07, p value?=?0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value?=?1.4?×?10^–13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

     

Enolase 1 of Candida albicans binds human CD4+ T cells and modulates naïve and memory responses

To obtain a better understanding of the biology behind life-threatening fungal infections caused by Candida albicans, we recently conducted an in silico screening for fungal and host protein interaction partners. We report here that the extracellular domain of human CD4 binds to the moonlighting protein enolase 1 (Eno1) of C. albicans as predicted bioinformatically. By using different anti-CD4 monoclonal antibodies, we determined that C. albicans Eno1 (CaEno1) primarily binds to the extracellular domain 3 of CD4. Functionally, we observed that CaEno1 binding to CD4 activated lymphocyte-specific protein tyrosine kinase (LCK), which was also the case for anti-CD4 monoclonal antibodies tested in parallel. CaEno1 binding to naïve human CD4⁺ T cells skewed cytokine secretion toward a Th2 profile indicative of poor fungal control. Moreover, CaEno1 inhibited human memory CD4⁺ T-cell recall responses. Therapeutically, CD4⁺ T cells transduced with a p41/Crf1-specific T-cell receptor developed for adoptive T-cell therapy were not inhibited by CaEno1 in vitro. Together, the interaction of human CD4⁺ T cells with CaEno1 modulated host CD4⁺ T-cell responses in favor of the fungus. Thus, CaEno1 mediates not only immune evasion through its interference with complement regulators but also through the direct modulation of CD4⁺ T-cell responses.     

WHO stufe II—Klinische Realität oder didaktisches Instrument?

INTRODUCTION: In 1986 the World Health Organisation (WHO) proposed an analgesic ladder for the effective therapy of cancer pain. The three standard analgesics making up this ladder are aspirin (non-opioid), codeine (weak opioid) and morphine (strong opioid). Adjuvant drugs may be added at any level. However, before 1986 step II analgesics (weak opioids) had never been tested in cancer pain relief. METHODS: This report presents a computer-assisted Medline (US National Library of Medicine) literature search restricted to the years 1986-1994, which was conducted to test the validity of the WHO guidelines, and in particular that of step II. RESULTS: We found seven retrospective studies and one prospective study on cancer pain treatment according to the proposed WHO guidelines that had been published since 1986. Every publication decribed the use of all three steps of the analgesic ladder. We found no prospective controlled trials demonstrating the efficacy and safety of WHO step II in particular. DISCUSSION: The use of the WHO guidelines "by mouth, by the clock and by the ladder" is now the mainstay of cancer pain management. Because of the guidelines' simplicity they found general acceptance and helped to establish an international pain therapy standard for worldwide use. Nevertheless, there is no scientific validation of WHO step II. In the absence of prospective controlled randomized trials additional longterm results are necessary. We need more data on the use of WHO step II and an update of the published guidelines taking account of modern sustained-release drugs. Up to now, step II of the WHO guidelines for cancer pain is not a clinical reality but at best a didactic instrument.     

Selective incorporation of111In-labeled PHOTOFRIN™ by glioma tissuein vivo

The use of PHOTOFRIN for photodynamic therapy of human gliomas has been studied by i.v. administration and laser photosensitization. Defining the uptake of PHOTOFRIN in the patient's tumor in comparison with the surrounding normal brain tissue is highly desirable for patient selection and study ofin vivo kinetics. We utilized a non-invasive approach to the detection of PHOTOFRIN uptake in brain tumors with¹¹¹In-oxine radiolabeled PHOTOFRIN and external imaging and quantitation using a gamma camera. Biodistribution of¹¹¹In-labeled PHOTOFRIN in 13 organs was determined in four dogs and 15 mice with gliomas.^99mTc-DTPA was used as a control for nonspecific uptake. The greatest concentration of¹¹¹In-PHOTOFRIN in the brain tumor occurred at 24 hours post i.v. administration. The brain tumor PHOTOFRIN uptake was seven times greater than that of normal brain. The decreased blood background at 72 hours made this the optimum time for imaging. Specific tumor tissue uptake of¹¹¹In-PHOTOFRIN occurred, well beyond that resulting from blood-brain-barrier (BBB) breakdown.     

Reliability of level of care decisions in a Long-Term Care program

This paper addresses the question of the degree of agreement between experienced assessors making level-of-care placement decisions for the same client, given a comparable opportunity to obtain and record client information in a community-based Long-Term Care program.A systematic sample of 246 cases was selected, consisting of 47 preadmission assessments and 199 reviews. The resulting data were subjected to analysis using the statistic Kappa and the degree of agreement categories suggested by Fleiss.¹ It was found that at the level-of-care extremes— Extended Care and Personal Care—the agreement between two nurse assessors for reviews could be considered excellent. In the Intermediate Care range, however, the reliability of the level-of-care decision can only be considered fair. Agreement for initial assessments was less, withK=0.469 indicating, overall, only fair agreement. While there was most often only a one-care-level difference between assessors, the program assessor tended to recommend a higher level than the study or check assessor. This has implications for funding agencies and/or facility planners who must assess the likely care requirements of an increasing number of disabled elderly. From a program management perspective, the preceding analyses allow an objective judgement of the extent of the placement decision problem, if any, and further provide a definition of areas most in need of revision. The value of collaboration between practitioner and researcher is evident in these analyses.Dr. Stark is Director, Division of Health Services Research and Development and Assistant Professor, Department of Health Care and Epidemiology, The University of British Columbia. Dr. Gutman is Director, Gerontology Centre and Associate Professor, Faculty of Interdisciplinary Studies, Simon Fraser University. Dr. Brothers is Research Associate, Division of Health Systems, The University of British Columbia. Address enquiries to Dr. A. Stark, Director, Division of Health Services Research and Development, Office of the Coordinator of Health Sciences, The John F. McCreary Health Sciences Centre, 2194 Health Sciences Mall, The University of British Columbia, Vancouver, B.C., V6T 1Z6.The research described in this paper, as well as the larger study of which it is a part, is supported by a grant from the B.C. Health Care Research Foundation. In addition, the cooperation and support of the Ministry of Health, Province of British Columbia is gratefully acknowledged.