Atherosclerosis in the circle of Willis: Spatial differences in composition and in distribution of plaques

AbstractBackground and aimsIntracranial atherosclerosis is one of the main causes of ischemic stroke. However, the characteristics of intracranial arteries and atherosclerosis have rarely been studied. Therefore, we systematically investigated atherosclerotic changes in all arteries of the Circle of Willis (CoW).MethodsSixty-seven CoWs obtained at autopsy from randomly chosen hospital patients (mean age, 67.3 ± 12.5 years), of which a total of 1220 segments were collected from 22 sites. Atherosclerotic plaques were classified according to the revised American Heart Association classification and were related to local vessel characteristics, such as the presence of an external and internal elastic lamina and the elastic fibre density of the media.Results181 out of the 1220 segments had advanced plaques (15%), which were mainly observed in large arteries such as the internal carotid, middle cerebral, basilar and vertebral artery. Only 11 out of 1220 segments (1%) showed complicated plaques (p < 0.001). Six of these were intraplaque hemorrhages (IPH) and observed only in patients who had cardiovascular-related events (p = 0.015). The frequency of characteristics such as the external elastic lamina and a high elastin fibre density in the media was most often associated with the vertebral artery. Only 3% (n = 33) of the CoW arteries contained calcification (p < 0.001), which were mostly observed in the vertebral artery (n = 13, 12%).ConclusionsAdvanced atherosclerotic plaques in the CoW are relatively scarce and mainly located in the 4 large arteries, and mostly characterized by an early and stable phenotype, a low calcific burden, and a low frequency of IPH

Overrepresentation of IL-17A and IL-22 Producing CD8 T Cells in Lesional Skin Suggests Their Involvement in the Pathogenesis of Psoriasis

Background: Although recent studies indicate a crucial role for IL-17A and IL-22 producing T cells in the pathogenesis of psoriasis, limited information is available on their frequency and heterogeneity and their distribution in skin in situ. Methodology/Principal Findings: By spectral imaging analysis of double-stained skin sections we demonstrated that IL-17 was mainly expressed by mast cells and neutrophils and IL-22 by macrophages and dendritic cells. Only an occasional IL-17(pos), but no IL-22(pos) T cell could be detected in psoriatic skin, whereas neither of these cytokines was expressed by T cells in normal skin. However, examination of in vitro-activated T cells by flow cytometry revealed that substantial percentages of skin-derived CD4 and CD8 T cells were able to produce IL-17A alone or together with IL-22 (i.e. Th17 and Tc17, respectively) or to produce IL-22 in absence of IL-17A and IFN-gamma (i.e. Th22 and Tc22, respectively). Remarkably, a significant proportional rise in Tc17 and Tc22 cells, but not in Th17 and Th22 cells, was found in T cells isolated from psoriatic versus normal skin. Interestingly, we found IL-22 single-producers in many skin-derived IL-17A(pos) CD4 and CD8 T cell clones, suggesting that in vivo IL-22 single-producers may arise from IL-17A(pos) T cells as well. Conclusions/Significance: The increased presence of Tc17 and Tc22 cells in lesional psoriatic skin suggests that these types of CD8 T cells play a significant role in the pathogenesis of psoriasis. As part of the skin-derived IL-17A(pos) CD4 and CD8 T clones developed into IL-22 single-producers, this demonstrates plasticity in their cytokine production profile and suggests a developmental relationship between Th17 and Th22 cells and between Tc17 and Tc22 cell

Correction:Variability and cost implications of three generations of the Roche LightCycler® 480

[This corrects the article DOI: 10.1371/journal.pone.0190847.]

Locally increased P-glycoprotein function in major depression: a PET study with [C-11]verapamil as a probe for P-glycoprotein function in the blood-brain barrier

The aetiology of depressive disorder remains unknown, although genetic susceptibility and exposure to neurotoxins are currently being discussed as possible contributors to this disorder. In normal circumstances, the brain is protected against bloodborne toxic influences by the blood-brain barrier, which includes the molecular efflux pump P-glycoprotein (P-gp) in the vessel wall of brain capillaries. We hypothesized that P-gp function in the blood-brain barrier is changed in patients with major depression. Positron emission tomography Was used to measure brain uptake of [C-11]verapamil, which is normally expelled from the brain by P-gp. Cerebral Volume of distribution (V-T) of [C-11]verapamil was used as a measure of P-gp function. Both region-of-interest (ROI) analysis and voxel analysis using statistical parametric mapping (SPM2) were performed to assess regional brain P-gp function. We found that patients with a major depressive episode, using antidepressants, compared to health), controls showed a significant decrease of [C-11]verapamil uptake in different areas throughout the brain, in particular in frontal and temporal regions. The decreased [C-11]verapamil uptake correlates with an increased function of the P-gp protein and may be related to chronic use of psychotropic drugs, Our results may explain why treatment-resistant depression can develop

Low Numbers of FOXP3 Positive Regulatory T Cells Are Present in all Developmental Stages of Human Atherosclerotic Lesions

BACKGROUND: T cell mediated inflammation contributes to atherogenesis and the onset of acute cardiovascular disease. Effector T cell functions are under a tight control of a specialized T cell subset, regulatory T cells (Treg). At present, nothing is known about the in situ presence of Treg in human atherosclerotic tissue. In the present study we investigated the frequency of naturally occurring Treg cells in all developmental stages of human atherosclerotic lesions including complicated thrombosed plaques. METHODOLOGY: Normal arteries, early lesions (American Heart Association classification types I, II, and III), fibrosclerotic plaques (types Vb and Vc) and 'high risk' plaques (types IV, Va and VI) were obtained at surgery and autopsy. Serial sections were immunostained for markers specific for regulatory T cells (FOXP3 and GITR) and the frequency of these cells was expressed as a percentage of the total numbers of CD3+ T cells. Results were compared with Treg counts in biopsies of normal and inflammatory skin lesions (psoriasis, spongiotic dermatitis and lichen planus). PRINCIPLE FINDINGS: In normal vessel fragments T cells were virtually absent. Treg were present in the intima during all stages of plaque development (0.5-5%). Also in the adventitia of atherosclerotic vessels Treg were encountered, in similar low amounts. High risk lesions contained significantly increased numbers of Treg compared to early lesions (mean: 3.9 and 1.2%, respectively). The frequency of FOXP3+ cells in high risk lesions was also higher compared to stable lesions (1.7%), but this difference was not significant. The mean numbers of intimal FOXP3 positive cells in atherosclerotic lesions (2.4%) was much lower than those in normal (24.3%) or inflammatory skin lesions (28%). CONCLUSION: Low frequencies of Treg in all developmental stages of human plaque formation could explain the smoldering chronic inflammatory process that takes place throughout the longstanding course of atherosclerosis

Concomitant intraperitoneal and systemic chemotherapy for extensive peritoneal metastases of colorectal origin: protocol of the multicentre, open-label, phase I, dose-escalation INTERACT trial

INTRODUCTION: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has become standard of care for patients with peritoneal metastases of colorectal origin with a low/moderate abdominal disease load. In case of a peritoneal cancer index (PCI) score >20, CRS-HIPEC is not considered to be beneficial. Patients with a PCI >20 are currently offered palliative systemic chemotherapy. Previous studies have shown that systemic chemotherapy is less effective against peritoneal metastases than it is against haematogenous spread of colorectal cancer. It is suggested that patients with peritoneal metastases may benefit from the addition of intraperitoneal chemotherapy to systemic chemotherapy. Aim of this study is to establish the maximum tolerated dose of intraperitoneal irinotecan, added to standard of care systemic therapy for colorectal cancer. Secondary endpoints are to determine the safety and feasibility of this treatment and to establish the pharmacokinetic profile of intraperitoneally administered irinotecan. METHODS AND ANALYSIS: This phase I, '3+3' dose-escalation, study is performed in two Dutch tertiary referral centres. The study population consists of adult pa

Effects of a short individually tailored counselling session for HIV prevention in gay and bisexual men receiving Hepatitis B vaccination

Background. There is currently a trend towards unsafe unprotected anal intercourse (UAI) among men who have sex with men. We evaluated a short individual counselling session on reducing UAI among gay and bisexual men. Methods. A quasi-experimental design was used to evaluate the counselling session. This session was conducted during consulting hours at four municipal health clinics during a Hepatitis B vaccination campaign. These clinics offered free vaccination to high-risk groups, such as gay and bisexual men. All gay and bisexual men attending health clinics in four cities in the Netherlands were asked to participate. Each participant in the intervention group received a fifteen-minute individual counselling based on the Theory of Planned Behaviour and Motivational Interviewing. Changes in UAI were measured over a 5-months period, using self-administered questionnaires. UAI was measured separately for receptive and insertive intercourse in steady and casual partners. These measures were combined in an index-score (range 0-8). Results. While UAI in the counselling group remained stable, it increased in the controls by 66% from 0.41 to 0.68. The results show that the intervention had a protective effect on sexual behaviour with steady partners. Intervention effects were strongest within steady relationships, especially for men whose steady-relationship status changed during the study. The intervention was well accepted among the target group. Conclusion. The fifteen-minute individually tailored counselling session was not only well accepted but also had a protective effect on risk behaviour after a follow-up of six months