HLA-DR expression on monocytes and systemic inflammation in patients with ruptured abdominal aortic aneurysms

INTRODUCTION: Mortality from ruptured abdominal aortic aneurysms (RAAA) remains high. Severe systemic inflammation, leading to multi-organ failure, often occurs in these patients. In this study we describe the level of HLA-DR expression in a consecutive group of patients following surgery for RAAA and compare results between survivors and non-survivors. A similar comparison is made for IL-6 and IL-10 levels and Sequential Organ Failure Assessment (SOFA) scores. METHODS: This is a prospective observational study. Patients with RAAA were prospectively analysed. Blood samples were collected on days 1, 3, 5, 7, 10 and 14. The fraction of CD-14 positive monocytes expressing HLA-DR was measured by flow-cytometry. IL-6 and IL-10 levels were measured by ELISA. RESULTS: The study included 30 patients with a median age of 70 years, of which 27 (90%) were men. Six patients died from multiple organ failure, all other patients survived. The SOFA scores were significantly higher in non-survivors on days 1 through 14. HLA-DR expression on monocytes was significantly lower on days 3, 5, 7, 10 and 14 in non-survivors. IL-6 and IL-10 levels were significantly higher in non-survivors on day 1 and days 1 and 3, respectively. CONCLUSION: HLA-DR expression on monocytes was decreased, especially in non-survivors. All patients with RAAA displayed a severe inflammatory and anti-inflammatory response with an increased production of IL-6 and IL-10. Poor outcome is associated with high levels of IL-6 and IL-10 and a high SOFA score in the first three days after surgery, while low levels of HLA-DR expression are observed from day three after RAAA repair

Case finding of mild cognitive impairment and dementia and subsequent care; results of a cluster RCT in primary care

Purpose Despite a call for earlier diagnosis of dementia, the diagnostic yield of case finding and its impact on the mental health of patients and relatives are unclear. This study assessed the effect of a two-component intervention of case finding and subsequent care on these outcomes. Methods In a cluster RCT we assessed whether education of family physicians (FPs; trial stage 1) resulted in more mild cognitive impairment (MCI) and dementia diagnoses among older persons in whom FPs suspected cognitive decline and whether case finding by a practice nurse and the FP (trial stage 2) added to this number of diagnoses. In addition, we assessed mental health effects of case finding and subsequent care (trial stage 2). FPs of 15 primary care practices (PCPs = clusters) judged the cognitive status of all persons ≤ 65 years. The primary outcome, new MCI and dementia diagnoses by FPs after 12 months as indicated on a list, was assessed among all persons in whom FPs suspected cognitive impairment but without a formal diagnosis of dementia. The secondary outcome, mental health of patients and their relatives, was assessed among persons consenting to participate in trial stage 2. Trial stage 1 consisted of either intervention component 1: training FPs to diagnose MCI and dementia, or control: no training. Trial stage 2 consisted of either intervention component 2: case finding of MCI and dementia and care by a trained nurse and the FP, or control: care as usual. Results Seven PCPs were randomized to the intervention; eight to the control condition. MCI or dementia was diagnosed in 42.3 (138/326) of persons in the intervention, and in 30.5 (98/321) in the control group (estimated difference GEE: 10.8, OR: 1.51, 95-CI 0.60-3.76). Among patients and relatives who consented to stage 2 of the trial (n = 145; 25), there were no differences in mental health between the intervention and control group. Conclusions We found a non-significant increase in the number of new MCI diagnoses. As we cannot exclude a clinically relevant effect, a larger study is warranted to replicate ours. Trial Registration Nederlands Trial Register NTR3389 © 2016 van den Dungen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Particle Physics from Almost Commutative Spacetimes

Our aim in this review article is to present the applications of Connes' noncommutative geometry to elementary particle physics. Whereas the existing literature is mostly focused on a mathematical audience, in this article we introduce the ideas and concepts from noncommutative geometry using physicists' terminology, gearing towards the predictions that can be derived from the noncommutative description. Focusing on a light package of noncommutative geometry (so-called 'almost commutative manifolds'), we shall introduce in steps: electrodynamics, the electroweak model, culminating in the full Standard Model. We hope that our approach helps in understanding the role noncommutative geometry could play in describing particle physics models, eventually unifying them with Einstein's (geometrical) theory of gravity.Comment: 104 pages, 5 figures, version 2 (minor changes and some additional references

Case-finding of dementia in general practice and effects of subsequent collaborative care; design of a cluster RCT

<p>Abstract</p> <p>Background</p> <p>In the primary care setting, dementia is often diagnosed relatively late in the disease process. Case finding and proactive collaborative care may have beneficial effects on both patient and informal caregiver by clarifying the cause of cognitive decline and changed behaviour and by enabling support, care planning and access to services.</p> <p>We aim to improve the recognition and diagnosis of individuals with dementia in general practice. In addition to this diagnostic aim, the effects of case finding and subsequent care on the mental health of individuals with dementia and the mental health of their informal carers are explored.</p> <p>Methods and design</p> <p>Design: cluster randomised controlled trial with process evaluation.</p> <p>Participants: 162 individuals ≥ 65 years, in 15 primary care practices, in whom GPs suspect cognitive impairment, but without a dementia diagnosis.</p> <p>Intervention; case finding and collaborative care: 2 trained practice nurses (PNs) invite all patients with suspected cognitive impairment for a brief functional and cognitive screening. If the cognitive tests are supportive of cognitive impairment, individuals are referred to their GP for further evaluation. If dementia is diagnosed, a comprehensive geriatric assessment takes place to identify other relevant geriatric problems that need to be addressed. Furthermore, the team of GP and PN provide information and support.</p> <p>Control: GPs provide care and diagnosis as usual.</p> <p>Main study parameters: after 12 months both groups are compared on: 1) incident dementia (and MCI) diagnoses and 2) patient and caregiver quality of life (QoL-AD; EQ5D) and mental health (MH5; GHQ 12) and caregiver competence to care (SSCQ). The process evaluation concerns facilitating and impeding factors to the implementation of this intervention. These factors are assessed on the care provider level, the care recipient level and on the organisational level.</p> <p>Discussion</p> <p>This study will provide insight into the diagnostic yield and the clinical effects of case finding and collaborative care for individuals with suspected cognitive impairment, compared to usual care. A process evaluation will give insight into the feasibility of this intervention.</p> <p>The first results are expected in the course of 2013.</p> <p>Trial registration</p> <p>NTR3389</p

A survey of spectral models of gravity coupled to matter

This is a survey of the historical development of the Spectral Standard Model and beyond, starting with the ground breaking paper of Alain Connes in 1988 where he observed that there is a link between Higgs fields and finite noncommutative spaces. We present the important contributions that helped in the search and identification of the noncommutative space that characterizes the fine structure of space-time. The nature and properties of the noncommutative space are arrived at by independent routes and show the uniqueness of the Spectral Standard Model at low energies and the Pati-Salam unification model at high energies.Comment: An appendix is added to include scalar potential analysis for a Pati-Salam model. 58 Page

Three-year survival of single- and two-surface ART restorations in a high-caries child population

The aim of this study was to evaluate the survival of single- and two-surface atraumatic restorative treatment (ART) restorations in the primary and permanent dentitions of children from a high-caries population, in a field setting. The study was conducted in the rainforest of Suriname, South America. ART restorations, made by four Dutch dentists, were evaluated after 6 months, 1, 2, and 3 years. Four hundred seventy-five ART restorations were placed in the primary dentition and 54 in first permanent molars of 194 children (mean age 6.09 ± 0.48 years). Three-year cumulative survivals of single- and two-surface ART restorations in the primary dentition were 43.4 and 12.2%, respectively. Main failure characteristics were gross marginal defects and total or partial losses. Three-year cumulative survival for single-surface ART restorations in the permanent dentition was 29.6%. Main failure characteristics were secondary caries and gross marginal defects. An operator effect was found only for two-surface restorations. The results show extremely low survival rates for single- and two-surface ART restorations in the primary and permanent dentitions. The variable success for ART may initiate further discussion about alternative treatment strategies, especially in those situations where choices have to be made with respect to a well-balanced, cost-effective package of basic oral health care

An evaluation of primary care led dementia diagnostic services in Bristol

© 2014 Dodd et al. Background: Typically people who go to see their GP with a memory problem will be initially assessed and those patients who seem to be at risk will be referred onto a memory clinic. The demographic forces mean that memory services will need to expand to meet demand. An alternative may be to expand the role of primary care in dementia diagnosis and care. The aim of this study was to contrast patient, family member and professional experience of primary and secondary (usual) care led memory services. Methods: A qualitative, participatory study. A topic guide was developed by the peer and professional panels. Data were collected through peer led interviews of people with dementia, their family members and health professionals. Results: Eleven (21%) of the 53 GP practices in Bristol offered primary care led dementia services. Three professional panels were held and were attended by 9 professionals; nine carers but no patients were involved in the three peer panels. These panels identified four main themes: GPS rarely make independent dementia diagnosis; GPS and memory nurses work together; patients and carers generally experience a high quality diagnostic service; an absence of post diagnostic support. Evidence relating to these themes was collected through a total of 46 participants took part; 23 (50%) in primary care and 23 (50%) in the memory service. Conclusions: Patients and carers were generally satisfied with either primary or secondary care led approaches to dementia diagnosis. Their major concern, shared with many health care professionals, was a lack of post diagnostic support

The accumulation of erythrocytes quantified and visualized by Glycophorin C in carotid atherosclerotic plaque reflects intraplaque hemorrhage and pre-procedural neurological symptoms

The accumulation of erythrocyte membranes within an atherosclerotic plaque may contribute to the deposition of free cholesterol and thereby the enlargement of the necrotic core. Erythrocyte membranes can be visualized and quantified in the plaque by immunostaining for the erythrocyte marker glycophorin C. Hence, we theorized that the accumulation of erythrocytes quantified by glycophorin C could function as a marker for plaque vulnerability, possibly reflecting intraplaque hemorrhage (IPH), and offering predictive value for pre-procedural neurological symptoms. We employed the CellProfiler-integrated slideToolKit workflow to visualize and quantify glycophorin C, defined as the total plaque area that is positive for glycophorin C, in single slides of culprit lesions obtained from the Athero-Express Biobank of 1819 consecutive asymptomatic and symptomatic patients who underwent carotid endarterectomy. Our assessment included the evaluation of various parameters such as lipid core, calcifications, collagen content, SMC content, and macrophage burden. These parameters were evaluated using a semi-quantitative scoring method, and the resulting data was dichotomized as predefined criteria into categories of no/minor or moderate/heavy staining. In addition, the presence or absence of IPH was also scored. The prevalence of IPH and pre-procedural neurological symptoms were 62.4% and 87.1%, respectively. The amount of glycophorin staining was significantly higher in samples from men compared to samples of women (median 7.15 (IQR:3.37, 13.41) versus median 4.06 (IQR:1.98, 8.32), p < 0.001). Glycophorin C was associated with IPH adjusted for clinical confounders (OR 1.90; 95% CI 1.63, 2.21; p =  < 0.001). Glycophorin C was significantly associated with ipsilateral pre-procedural neurological symptoms (OR:1.27, 95%CI:1.06-1.41, p = 0.005). Sex-stratified analysis, showed that this was also the case for men (OR 1.37; 95%CI 1.12, 1.69; p = 0.003), but not for women (OR 1.15; 95%CI 0.77, 1.73; p = 0.27). Glycophorin C was associated with classical features of a vulnerable plaque, such as a larger lipid core, a higher macrophage burden, less calcifications, a lower collagen and SMC content. There were marked sex differences, in men, glycophorin C was associated with calcifications and collagen while these associations were not found in women. To conclude, the accumulation of erythrocytes in atherosclerotic plaque quantified and visualized by glycophorin C was independently associated with the presence of IPH, preprocedural symptoms in men, and with a more vulnerable plaque composition in both men and women. These results strengthen the notion that the accumulation of erythrocytes quantified by glycophorin C can be used as a marker for plaque vulnerability

Long-Term Locoregional Vascular Morbidity After Isolated Limb Perfusion and External-Beam Radiotherapy for Soft Tissue Sarcoma of the Extremity

Background: Isolated limb perfusion (ILP) with tumor necrosis factor alpha (TNF-alpha) and melphalan, followed by delayed surgical resection and adjuvant external-beam radiotherapy is a limb salvage treatment strategy for locally advanced soft tissue sarcomas. The long-term vascular side effects of this combined procedure were evaluated. Methods: Thirty-two patients were treated for a locally advanced sarcoma of the upper (n = 5) or lower limb (n = 27). All patients underwent a noninvasive vascular work-up. Results: Five patients underwent a leg amputation, in two cases due to critical leg ischemia 10 years after ILP. With a median follow-up of 88 (range, 17-159) months, none of the patients with a salvaged lower leg (n = 22) experienced peripheral arterial occlusive disease. Ankle-brachial index (ABI) measurements in the involved leg (median, 1.02; range, .50-1.20) showed a significant decrease compared with the contralateral leg (median, 1.09; range, .91-1.36, P = .001). Pulsatility index (PI) was decreased in the treated leg in 17 of 22 patients at the femoral level (median, 6.30; range, 2.1-23.9 vs. median, 7.35; range, 4.8-21.9; P = .011) and in 19 of 20 patients at popliteal level (median, 8.35; range, 0-21.4 vs. median, 10.95; range, 8.0-32.6; P <.0005). In patients with follow-up of > 5 years, there was more often a decrease in ABI (P = .024) and PI at femoral level (P = .011). Conclusions: ILP followed by resection and external-beam radiotherapy can lead to major late vascular morbidity that requires amputation. Objective measurements show a time-related decrease of ABI and femoral PI in the treated extremity

N6-Methyladenosine Promotes TNF mRNA Degradation In CD4+ T Lymphocytes

N6-methyladenosine (m6A) is a RNA modification that can regulate post-transcriptional processes including RNA stability, translation, splicing, and nuclear export. In CD4+ lymphocytes, m6A modifications have been demonstrated to play a role in early differentiation processes. The role of m6A in CD4+ T cell activation and effector function remains incompletely understood. To assess the role of m6A in CD4+ T lymphocyte activation and function, we assessed the transcriptome-wide m6A landscape of human primary CD4+ T cells by methylated RNA immunoprecipitation sequencing. Stimulation of the T cells impacted the m6A pattern of hundreds of transcripts including tumor necrosis factor (TNF). m6A methylation was increased on TNF messenger RNA (mRNA) after activation, predominantly in the 3' untranslated region of the transcript. Manipulation of m6A levels in primary human T cells, the directly affected the expression of TNF. Furthermore, we identified that the m6A reader protein YTHDF2 binds m6A-methylated TNF mRNA, and promotes its degradation. Taken together, this study demonstrates that TNF expression in CD4+ T lymphocytes is regulated via m6A and YTHDF2, thereby providing novel insight into the regulation of T cell effector functions