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This article looks at some of the strategies of enforcing tax compliance in the Netherlands. It discusses the efforts of tax authorities to prevent the evasion of paying taxes through the invention and implementation of tax avoiding constructions. It also explores how tax authorities manage tax risks and the enforcement of the concept of a tax control framework. In additon, the article describes the tax risk management and reporting functionalities included in the integrated risk management framework.

Objectives: To compare diagnostic accuracy of a deep learning artificial intelligence (AI) for cervical spine (C-spine) fracture detection on CT to attending radiologists and assess which undetected fractures were injuries in need of stabilising therapy (IST)., Methods: This single-centre, retrospective diagnostic accuracy study included consecutive patients (age ≥18 years; 2007-2014) screened for C-spine fractures with CT. To validate ground truth, one radiologist and three neurosurgeons independently examined scans positive for fracture. Negative scans were followed up until 2022 through patient files and two radiologists reviewed negative scans that were flagged positive by AI. The neurosurgeons determined which fractures were ISTs. Diagnostic accuracy of AI and attending radiologists (index tests) were compared using McNemar., Results: Of the 2368 scans (median age, 48, interquartile range 30-65; 1441 men) analysed, 221 (9.3%) scans contained C-spine fractures with 133 IST. AI detected 158/221 scans with fractures (sensitivity 71.5%, 95% CI 65.5-77.4%) and 2118/2147 scans without fractures (specificity 98.6%, 95% CI 98.2-99.1). In comparison, attending radiologists detected 195/221 scans with fractures (sensitivity 88.2%, 95% CI 84.0-92.5%, p < 0.001) and 2130/2147 scans without fracture (specificity 99.2%, 95% CI 98.8-99.6, p = 0.07). Of the fractures undetected by AI 30/63 were ISTs versus 4/26 for radiologists. AI detected 22/26 fractures undetected by the radiologists, including 3/4 undetected ISTs., Conclusion: Compared to attending radiologists, the artificial intelligence has a lower sensitivity and a higher miss rate of fractures in need of stabilising therapy; however, it detected most fractures undetected by the radiologists, including fractures in need of stabilising therapy. Clinical relevance statement The artificial intelligence algorithm missed more cervical spine fractures on CT than attending radiologists, but detected 84.6% of fractures undetected by radiologists, including fractures in need of stabilising therapy., Key Points: The impact of artificial intelligence for cervical spine fracture detection on CT on fracture management is unknown. The algorithm detected less fractures than attending radiologists, but detected most fractures undetected by the radiologists including almost all in need of stabilising therapy. The artificial intelligence algorithm shows potential as a concurrent reader., (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Objectives: Virtual monochromatic images (VMI) are increasingly used in clinical practice as they improve contrast-to-noise ratio. However, due to their different appearances, the performance of artificial intelligence (AI) trained on conventional CT images may worsen. The goal of this study was to assess the performance of an established AI algorithm trained on conventional polychromatic computed tomography (CT) images (CPI) to detect pulmonary embolism (PE) on VMI., Methods: Paired 60 kiloelectron volt (keV) VMI and CPI of 114 consecutive patients suspected of PE, obtained with a detector-based spectral CT scanner, were retrospectively analyzed by an established AI algorithm. The CT pulmonary angiography (CTPA) were classified as positive or negative for PE on a per-patient level. The reference standard was established using a comprehensive method that combined the evaluation of the attending radiologist and three experienced cardiothoracic radiologists aided by two different detection tools. Sensitivity, specificity, positive and negative predictive values and likelihood ratios of the algorithm on VMI and CPI were compared., Results: The prevalence of PE according to the reference standard was 35.1% (40 patients). None of the diagnostic accuracy measures of the algorithm showed a significant difference between CPI and VMI. Sensitivity was 77.5% (95% confidence interval (CI) 64.6-90.4%) and 85.0% (73.9-96.1%) (p = 0.08) on CPI and VMI respectively and specificity 96.0% (91.4-100.0%) and 94.6% (89.4-99.7%) (p = 0.32)., Conclusions: Diagnostic performance of the AI algorithm that was trained on CPI did not drop on VMI, which is reassuring for its use in clinical practice., Clinical Relevance Statement: A commercially available AI algorithm, trained on conventional polychromatic CTPA, could be safely used on virtual monochromatic images. This supports the sustainability of AI-aided detection of PE on CT despite ongoing technological advances in medical imaging, although monitoring in daily practice will remain important., Key Points: • Diagnostic accuracy of an AI algorithm trained on conventional polychromatic images to detect PE did not drop on virtual monochromatic images. • Our results are reassuring as innovations in hardware and reconstruction in CT are continuing, whilst commercial AI algorithms that are trained on older generation data enter healthcare., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Objective: Characterization of the atherosclerotic process fully relies on histological evaluation and staging through a consensus grading system. So far, a head-to-head comparison of atherosclerotic process in experimental models and tissue resources commonly applied in atherosclerosis research with the actual human atherosclerotic process is missing., Material and Methods: Aspects of the atherosclerotic process present in established murine atherosclerosis models and human carotid endarterectomy specimen were systematically graded using the modified American Heart Association histological classification (Virmani classification). Aspects were aligned with the atherosclerotic process observed in human coronary artery and aortic atherosclerosis reference tissues that were available through biobanks based on human tissue/organ donor material., Results: Apart from absent intraplaque hemorrhages in aortic lesions, the histological characteristics of the different stages of human coronary and aortic atherosclerosis are similar. Carotid endarterectomy samples all represent end-stage "fibrous calcified plaque" lesions, although secondary, progressive, and vulnerable lesions with gross morphologies similar to coronary/aortic lesions occasionally present along the primary lesions. For the murine lesions, clear histological parallels were observed for the intermediate lesion types ("pathological intimal thickening," and "early fibroatheroma"). However, none of the murine lesions studied progressed to an equivalent of late fibroatheroma or beyond. Notable contrasts were observed for disease initiation: whereas disease initiation in humans is characterized by a mesenchymal cell influx in the intima, the earliest murine lesions are exclusively intimal, with subendothelial accumulation foam cells. A mesenchymal (and medial) response are absent. In fact, it is concluded that the stage of "adaptive intimal thickening" is absent in all mouse models included in this study., Conclusions: The Virmani classification for coronary atherosclerosis can be applied for systematically grading experimental and clinical atherosclerosis. Application of this histological grading tool shows clear parallels for intermediate human and murine atherosclerotic lesions. However, clear contrasts are observed for disease initiation, and late stage atherosclerotic lesions. Carotid endarterectomy all represent end-stage fibrous calcified plaque lesions, although secondary earlier lesions may present in a subset of samples., (© 2023 by the Society for Vascular Surgery. Published by Elsevier Inc.)

Importance: There is a paucity of high-quality evidence about the long-term effects (ie, 3-5 years and beyond) of arthroscopic partial meniscectomy vs exercise-based physical therapy for patients with degenerative meniscal tears., Objectives: To compare the 5-year effectiveness of arthroscopic partial meniscectomy and exercise-based physical therapy on patient-reported knee function and progression of knee osteoarthritis in patients with a degenerative meniscal tear., Design, Setting, and Participants: A noninferiority, multicenter randomized clinical trial was conducted in the orthopedic departments of 9 hospitals in the Netherlands. A total of 321 patients aged 45 to 70 years with a degenerative meniscal tear participated. Data collection took place between July 12, 2013, and December 4, 2020., Interventions: Patients were randomly allocated to arthroscopic partial meniscectomy or 16 sessions of exercise-based physical therapy., Main Outcomes and Measures: The primary outcome was patient-reported knee function (International Knee Documentation Committee Subjective Knee Form (range, 0 [worst] to 100 [best]) during 5 years of follow-up based on the intention-to-treat principle, with a noninferiority threshold of 11 points. The secondary outcome was progression in knee osteoarthritis shown on radiographic images in both treatment groups., Results: Of 321 patients (mean [SD] age, 58 [6.6] years; 161 women [50.2%]), 278 patients (87.1%) completed the 5-year follow-up with a mean follow-up time of 61.8 months (range, 58.8-69.5 months). From baseline to 5-year follow-up, the mean (SD) improvement was 29.6 (18.7) points in the surgery group and 25.1 (17.8) points in the physical therapy group. The crude between-group difference was 3.5 points (95% CI, 0.7-6.3 points; P < .001 for noninferiority). The 95% CI did not exceed the noninferiority threshold of 11 points. Comparable rates of progression of radiographic-demonstrated knee osteoarthritis were noted between both treatments., Conclusions and Relevance: In this noninferiority randomized clinical trial after 5 years, exercise-based physical therapy remained noninferior to arthroscopic partial meniscectomy for patient-reported knee function. Physical therapy should therefore be the preferred treatment over surgery for degenerative meniscal tears. These results can assist in the development and updating of current guideline recommendations about treatment for patients with a degenerative meniscal tear., Trial Registration: ClinicalTrials.gov Identifier: NCT01850719.

Background The prognosis of hospitalized patients with severe coronavirus disease 2019 (COVID-19) is difficult to predict, and the capacity of intensive care units was a limiting factor during the peak of the pandemic and is generally dependent on a country's clinical resources. Purpose To determine the value of chest radiographic findings together with patient history and laboratory markers at admission to predict critical illness in hospitalized patients with COVID-19. Materials and Methods In this retrospective study, which included patients from March 7, 2020, to April 24, 2020, a consecutive cohort of hospitalized patients with real-time reverse transcription polymerase chain reaction-confirmed COVID-19 from two large Dutch community hospitals was identified. After univariable analysis, a risk model to predict critical illness (ie, death and/or intensive care unit admission with invasive ventilation) was developed, using multivariable logistic regression including clinical, chest radiographic, and laboratory findings. Distribution and severity of lung involvement were visually assessed by using an eight-point scale (chest radiography score). Internal validation was performed by using bootstrapping. Performance is presented as an area under the receiver operating characteristic curve. Decision curve analysis was performed, and a risk calculator was derived. Results The cohort included 356 hospitalized patients (mean age, 69 years ± 12 [standard deviation]; 237 men) of whom 168 (47%) developed critical illness. The final risk model's variables included sex, chronic obstructive lung disease, symptom duration, neutrophil count, C-reactive protein level, lactate dehydrogenase level, distribution of lung disease, and chest radiography score at hospital presentation. The area under the receiver operating characteristic curve of the model was 0.77 (95% CI: 0.72, 0.81; P < .001). A risk calculator was derived for individual risk assessment: Dutch COVID-19 risk model. At an example threshold of 0.70, 71 of 356 patients would be predicted to develop critical illness, of which 59 (83%) would be true-positive results. Conclusion A risk model based on chest radiographic and laboratory findings obtained at admission was predictive of critical illness in hospitalized patients with coronavirus disease 2019. This risk calculator might be useful for triage of patients to the limited number of intensive care unit beds or facilities. © RSNA, 2020 Online supplemental material is available for this article.

Background and Aims: With the intention to gain support for the hypothesis that incident ischemic complications of atherosclerotic disease involve a stochastic aspect, we performed a histological, qualitative evaluation of the epidemiology of coronary atherosclerotic disease in a cohort of aortic valve donors., Patients and Methods: Donors (n = 695, median age 54, range 11-65 years) were dichotomized into a non-cardiovascular (non-CVD) and a cardiovascular disease death (CVD) group. Consecutive 5 mm proximal left coronary artery segments were Movat stained, and the atherosclerotic burden for each segment was graded (revised AHA-classification)., Results: Non-CVD and CVD groups showed steep increase of atherosclerosis severity beyond the age of 40, resulting in an endemic presence of advanced atherosclerosis in men over 40 and women over 50 years. In fact, only 19% of the non-CVD and 6% of the CVD donors over 40 years were classified with a normal LCA or a so called non-progressive lesion type. Fibrous calcified plaques (FCP), the consolidated remnants of earlier ruptured lesions, dominated in both non-CVD and CVD donors. Estimates of the atherosclerosis burden (i.e. average lesion grade, proportion of FCPs, and average number of FCPs per cross-section) were all higher in the CVD group (p<1.10-16, p<0.0001, and p<0.05, respectively)., Conclusions: Dominance of consolidated FCP lesions in males over 40 and females over 50 years, show that plaque ruptures in the left coronary artery are common. However, the majority of these ruptures remain asymptomatic. This implies that the atherosclerotic process is repetitive. A relative difference in disease burden between CVD and non-CVD donors supports the concept that complications of atherosclerotic disease involve a stochastic element., Competing Interests: The authors have declared that no competing interests exist.

Atherosclerosis is a complex process with strong inflammatory component. We developed a straightforward sevenfold staining protocol for simultaneous assessment of dominant leukocyte classes, vascularization, and expression of the putative foam cell maker CD36. The method was applied on human coronaries covering the full spectrum of atherosclerotic disease. Results confirm the progressive association of macrophages and T cells with the process and a global presence of mast cells. B cells are exclusively present in adventitial follicles that accompany the process plaque destabilization (thin cap and ruptured lesions) and are otherwise absent. Neutrophils are only present as part of the hemorrhage that accompanies plaque rupture. This study does not classify CD36 as a key factor in foam cell formation. Observed macrophage accumulation in the neointima of stabilized fibrous calcified plaques is consistent with a process of neoatherosclerosis. This study on human coronaries shows a progressive association of macrophage and T-cell abundance with plaque progression. Follicle-like structures are transiently present during the process of plaque destabilization. Plaque healing is accompanied by cessation of the inflammatory response but followed by a new cycle of atherosclerosis., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background/objectives: Carotid intimal media thickness (IMT) and coronary calcium scores (CCS) are thought to reflect atherosclerotic burden. The validity of this assumption for IMT is challenged by recent meta-analyses; for CCS by absence of a relationship between negative scores, and freedom of future events. As such, we considered evaluation of the relationship between tissue IMT and CCS, and extend of atherosclerotic disease relevant., Methods: Analyses were performed on donor aortas obtained during renal graft procurement, and on coronary arteries collected during heart valve procurement for tissue donation. Movat pentachrome and Hematoxylin staining was performed, and the degree of atherosclerosis histologically graded. IMT and presence of calcium deposits were quantified on graded tissue sections., Results: 304 aortas and 185 coronary arteries covering the full atherosclerotic spectrum were evaluated. Aortas and coronaries showed similar relationships between tissue IMT and degree of atherosclerosis, with gradual increase in tissue IMT during earlier phases of atherosclerosis (r=0.68 and r=0.30, P<0.00001 for aorta and coronaries respectively), followed by plateauing of the curve in intermediate and advanced stages. Results for tissue IMT reveal high variability, resulting in wide confidence intervals. Results for CCS are similar for aorta and coronaries, with calcium depositions limited to advanced lesions., Conclusions: Histological IMT measurements for the aorta and coronaries show large variations around the trend and plateauing of, and possibly reductions in IMT in late stage atherosclerotic disease. These observations for the aorta and coronaries may (partly) explain the limited benefit of including carotid IMT in risk prediction algorithms., (Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: The concept of innate immunity is well recognized within the spectrum of atherosclerosis, which is primarily dictated by macrophages. Although current insights to this process are largely based on murine models, there are fundamental differences in the atherosclerotic microenvironment and associated inflammatory response relative to humans. In this light, we characterized the cellular aspects of innate immune response in normal, nonprogressive, and progressive human atherosclerotic plaques., Methods and Results: A systematic analysis of innate immune response was performed on 110 well-characterized human perirenal aortic plaques with immunostaining for specific macrophage subtypes (M1 and M2 lineage) and their activation markers, neopterin and human leukocyte antigen-antigen D related (HLA-DR), together with dendritic cells (DCs), natural killer (NK) cells, mast cells, neutrophils, and eosinophils. Normal aortae were devoid of low-density lipoprotein, macrophages, DCs, NK cells, mast cells, eosinophils, and neutrophils. Early, atherosclerotic lesions exhibited heterogeneous populations of (CD68(+)) macrophages, whereby 25% were double positive "M1" (CD68(+)/ inducible nitric oxide synthase [iNOS](+)/CD163(-)), 13% "M2" double positive (CD68(+)/iNOS(-)/CD163(+)), and 17% triple positive for (M1) iNOS (M2)/CD163 and CD68, with the remaining (≈40%) only stained for CD68. Progressive fibroatheromatous lesions, including vulnerable plaques, showed increasing numbers of NK cells and fascin-positive cells mainly localized to the media and adventitia whereas the M1/M2 ratio and level of macrophage activation (HLA-DR and neopterin) remained unchanged. On the contrary, stabilized (fibrotic) plaques showed a marked reduction in macrophages and cell activation with a concomitant decrease in NK cells, DCs, and neutrophils., Conclusions: Macrophage "M1" and "M2" subsets, together with fascin-positive DCs, are strongly associated with progressive and vulnerable atherosclerotic disease of human aorta. The observations here support a more complex theory of macrophage heterogeneity than the existing paradigm predicated on murine data and further indicate the involvement of (poorly defined) macrophage subtypes or greater dynamic range of macrophage plasticity than previously considered., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Experimental studies characterize adaptive immune response as a critical factor in the progression and complications of atherosclerosis. Yet, it is unclear whether these observations translate to the human situation. This study systematically evaluates cellular components of the adaptive immune response in a biobank of human aortas covering the full spectrum of atherosclerotic disease., Methods and Results: A systematic analysis was performed on 114 well-characterized perirenal aortic specimens with immunostaining for T-cell subsets (CD3/4/8/45RA/45RO/FoxP3) and the Th1/non-Th1/Th17 ratio (CD4(+)T-bet(+)/CD4(+)T-bet(-)/CD4(+)/interleukin-17(+) double staining). CD20 and CD138 were used to identify B cells and plasma cells, while B-cell maturation was evaluated by AID/CD21 staining and expression of lymphoid homeostatic CXCL13. Scattered CD4 and CD8 cells with a T memory subtype were found in normal aorta and early, nonprogressive lesions. The total number of T cells increases in progressive atherosclerotic lesions (≈1:5 CD4/CD8 T-cell ratio). A further increase in medial and adventitial T cells is found upon progression to vulnerable lesions.This critical stage is further hallmarked by de novo formation of adventitial lymphoidlike structures containing B cells and plasma cells, a process accompanied by transient expression of CXCL13. A dramatic reduction of T-cell subsets, disappearance of lymphoid structures, and loss of CXCL13 expression characterize postruptured lesions. FoxP3 and Th17 T cells were minimally present throughout the atherosclerotic process., Conclusions: Transient CXCL13 expression, restricted presence of B cells in human atherosclerosis, along with formation of nonfunctional extranodal lymphoid structures in the phase preceding plaque rupture, indicates a "critical" change in the inflammatory footprint before and during plaque destabilization., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Preoperative placement of self-expanding metal stents is used in patients with obstructing colon carcinoma to prevent an emergency operation. The perceived benefits remain the subject of discussion. The data-evaluating function and complications of stents in relation to radiological position are limited., Methods: Patients receiving a preoperative stent between 2003 and 2013 were retrospectively analysed in this single-centre study. We analysed radiological deployment, eccentricity and angulation of the stent directly after placement. Endpoints were clinical success (resolution of ileus), complications needing non-elective surgery (blow-out, perforation, persistent ileus, dislocation) and other complications (bleeding, infiltrate). Associations were corrected for other potential influences., Results: Eighty-two patients were included. In 22 patients (26.8%), the stent was placed proximal to the splenic flexure. Clinical success was present in 85.4%. Twenty-two patients (26.8%) had a complication of which 16 (19.5%) underwent urgent surgery for insufficient functioning of the stent; there were two blow-outs (2.4%). A more symmetrically placed stent was associated with clinical success (p = 0.042), with large overlap between groups. However, no association was found with non-elective surgery or complications. Also, angulation and deployment were unassociated with these outcomes., Conclusions: We could not establish an association between symmetry, angulation or deployment of self-expandable colonic stents with clinical success and complications., (© 2015 S. Karger AG, Basel.)

The relationships between oxidation-specific epitopes (OSE) and lipoprotein (a) [Lp(a)] and progressive atherosclerosis and plaque rupture have not been determined. Coronary artery sections from sudden death victims and carotid endarterectomy specimens were immunostained for apoB-100, oxidized phospholipids (OxPL), apo(a), malondialdehyde-lysine (MDA), and MDA-related epitopes detected by antibody IK17 and macrophage markers. The presence of OxPL captured in carotid and saphenous vein graft distal protection devices was determined with LC-MS/MS. In coronary arteries, OSE and apo(a) were absent in normal coronary arteries and minimally present in early lesions. As lesions progressed, apoB and MDA epitopes did not increase, whereas macrophage, apo(a), OxPL, and IK17 epitopes increased proportionally, but they differed according to plaque type and plaque components. Apo(a) epitopes were present throughout early and late lesions, especially in macrophages and the necrotic core. IK17 and OxPL epitopes were strongest in late lesions in macrophage-rich areas, lipid pools, and the necrotic core, and they were most specifically associated with unstable and ruptured plaques. Specific OxPL were present in distal protection devices. Human atherosclerotic lesions manifest a differential expression of OSEs and apo(a) as they progress, rupture, and become clinically symptomatic. These findings provide a rationale for targeting OSE for biotheranostic applications in humans.

Animal studies implicate the AP-1 (activator protein-1) pro-inflammatory pathway as a promising target in the treatment of atherosclerotic disease. It is, however, unclear whether these observations apply to human atherosclerosis. Therefore we evaluated the profile of AP-1 activation through histological analysis and tested the potential benefit of AP-1 inhibition in a clinical trial. AP-1 activation was quantified by phospho-c-Jun nuclear translocation (immunohistochemistry) on a biobank of aortic wall samples from organ donors. The effect of AP-1 inhibition on vascular parameters was tested through a double blind placebo-controlled cross-over study of 28 days doxycycline or placebo in patients with symptomatic peripheral artery disease. Vascular function was assessed by brachial dilation as well as by plasma samples analysed for hs-CRP (high-sensitivity C-reactive protein), IL-6 (interleukin-6), IL-8, ICAM-1 (intercellular adhesion molecule-1), vWF (von Willebrand factor), MCP-1 (monocyte chemoattractant protein-1), PAI-1 (plasminogen activator inhibitor-1) and fibrinogen. Histological evaluation of human atherosclerosis showed minimal AP-1 activation in non-diseased arterial wall (i.e. vessel wall without any signs of atherosclerotic disease). A gradual increase of AP-1 activation was found in non-progressive and progressive phases of atherosclerosis respectively (P<0.044). No significant difference was found between progressive and vulnerable lesions. The expression of phospho-c-Jun diminished as the lesion stabilized (P<0.016) and does not significantly differ from the normal aortic wall (P<0.33). Evaluation of the doxycycline intervention only revealed a borderline-significant reduction of circulating hs-CRP levels (-0.51 μg/ml, P=0.05) and did not affect any of the other markers of systemic inflammation and vascular function. Our studies do not characterize AP-1 as a therapeutic target for progressive human atherosclerotic disease.

Background: The TGF-β superfamily members transforming growth factor-β (TGF-β/Activin) and bone morphogenetic proteins (BMP) have been implicated in the pathogenesis of atherosclerosis. However, their role in human disease remains controversial. In this study we used Smad phosphorylation as a read out for TGF-β and BMP signaling during the initiation, progression and (de)stabilization of human atherosclerotic disease., Material and Methods: A systematic analysis was performed in 114 peri-renal aortic patches (stained with Movat Pentachrome, H&E, pSmad2, pSmad1,5,8 and PAI-1) covering the entire atherosclerotic spectrum (van Dijk, 2010). Immunostaining against T-cells (CD3) and monocytes and macrophages (CD68) was used to explore a putative association between TGF-β and BMP signaling and vascular inflammation., Results: Smad phosphorylation was present within the normal arterial wall in approximately 10% of the endothelial cells and intimal smooth muscle cells. A significant increase in pSmad2 and pSmad1,5,8 positivity was found in non-progressive lesions (>50% positivity). No further increase or decrease was found in the progressive atherosclerotic lesions, vulnerable and stabilized lesions. No association was found between TGF-β and BMP signaling and CD3 and CD68 expression, nor cap thickness., Conclusion: Activation of the TGF-β and BMP pathways is an early event in atherosclerotic lesion formation. No significant relationships were found between Smad phosphorylation and vessel wall inflammation or plaque vulnerability.

Background: Risk factor profiles for the different vascular beds (i.e. coronary, carotid, peripheral and aortic) are remarkably different, suggesting that atherosclerosis is a heterogeneous disorder. Little is known about the morphologic progression of atherosclerosis in the peri-renal aorta, one of the primary predilection sites of atherosclerosis., Methods: A systematic analysis was performed in 260 consecutive peri-renal aortic patches (stained with Movat Pentachrome and H&E) collected during organ transplantation (mean donor age 46.5 (range 5-76) years; 54% male symbol; mean BMI 24.9; 40% smokers; 20% hypertensive). Plaque morphology was classified according to the modified AHA classification scheme proposed by Virmani et al. [4]. Immunostaining against CD68 was used to identify the distribution of intimal macrophages and monocytes in several predefined locations among various plaque types and fibrous cap thickness., Results: There was significant intimal thickening (p<0.013) and medial thinning (p<0.032) with advancing age. The incidence of atherosclerotic plaques in the abdominal aorta correlated with age (r=0.640, p=0.01). During the first three decades of life adaptive intimal thickening and intimal xanthomas were the predominant lesions. In contrast, the fourth, fifth and sixth decades hallmarked more complicated plaques of pathological intimal thickening, early and late fibroatheromas (EFAs and LFAs), thin-cap FAs (TCFAs; cap thickness <155 microm), ruptured plaques (PRs), healed rupture and fibrotic calcified plaques. The mean percentage of lesional macrophages increased significantly from LFAs to TCFAs (5-17%; p<0.001). Macrophage infiltration of the fibrous cap was negatively correlated with fibrous cap thickness (p<0.0004); TCFAs and PRs (caps<100 microm) contained significantly more macrophages (19%) compared with caps 101-300 microm (6%) and >300 microm (2%). Macrophages in shoulder regions were highest in early and late FAs ( approximately 45%) followed by TCFAs (27%) and PR (20%). Further, intimal vasa vasorum were mostly seen adjacent to the necrotic core of advanced atherosclerotic plaques and remained confined to the intimo-medial border despite marked thickening of the intima., Conclusion: This study shows that peri-renal aortic atherosclerosis starts early in life. Gross plaque morphologies of the peri-renal abdominal aorta are similar to coronary atherosclerosis yet indications were found for site specific differences in macrophage content and neovascularization., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

We investigated the effects of aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril on left ventricular mass (LVM) index and arterial stiffness in hypertensive type II diabetic individuals. Seventy hypertensive type II diabetic individuals were treated with three antihypertensive strategies in a randomized, double-blind, double-dummy design. Blood pressure was titrated to levels below 130/85 mm Hg or a decrease in systolic pressure of 10% with a diastolic pressure below 85 mm Hg. After titration, patients were treated for 12 months. Mean blood pressures were 157/93, 151/94 and 149/93 mm Hg at baseline in the hydrochlorothiazide (n = 24), candesartan (n = 24) and lisinopril (n = 22) groups, and 135/80, 135/82 and 131/80 mm Hg after titration. About 70% reached target blood pressures, with the median use of three antihypertensive drugs. Left ventricular mass index and all estimates of arterial stiffness showed significant improvement after 12 months: that is, LVM index (-11 g/m(2); -8%); carotid distensibility coefficient (DC; +2.8 x 10(-3) kPa(-1); +27%), compliance coefficient (CC; +0.13 mm2/kPa; +21%) and elastic modulus (-0.19 kPa; -16%); femoral DC (+1.6 x 10(-3) kPa(-1); +50%) and CC (+0.08 mm2/kPa; +26%); brachial DC (+2.1 x 10(-3) kPa(-1); +39%) and CC (+0.03 mm2/kPa; +27%) and total systemic arterial compliance (+0.29 ml/mm Hg; +16%). No differences in outcome variables between treatment groups were observed. Aggressive antihypertensive treatment, although difficult to achieve, resulted in substantial reductions of LVM index and arterial stiffness in relatively uncomplicated hypertensive type II diabetic individuals. Strategies based on renin-angiotensin system inhibitors were not clearly superior to conventional (i.e. diuretic-based) strategies.

Background: Plasma levels of liver transaminases, including alanine aminotransferase (ALT), are elevated in most cases of nonalcoholic fatty liver disease (NAFLD). Elevated ALT levels are associated with insulin resistance, and subjects with NAFLD have features of the metabolic syndrome that confer high-risk cardiovascular disease. Alanine aminotransferase predicts the development of type 2 diabetes (DM2) in subjects with the metabolic syndrome. However, the role of elevated ALT levels in subjects with overt DM2 has yet not been explored., Materials and Methods: In a cross-sectional study, 64 normotriglyceridaemic subjects with DM2 were studied with regard to the relation between liver transaminases with whole-body insulin sensitivity, measured with the euglycaemic hyperinsulinaemic clamp and with brachial artery flow-mediated dilation (FMD) as a marker of endothelial dysfunction., Results: On average, patients were normotriglyceridaemic (plasma triglycerides 1.3 +/- 0.4 mmol L-1) and had good glycaemic control (HbA1c 6.2 +/- 0.8%). The mean ALT level was 15.0 +/- 7.5 U L-1, and the mean aspartate aminotransferase concentration equalled 10.6 +/- 2.6 U L-1. Alanine aminotransferase levels were negatively associated with whole-body insulin sensitivity as well as with FMD (both P = 0.03, in multivariate analyses; regression coefficients beta [95%CI]: -0.76 [-1.4 to -0.08] and -0.31 [-0.58 to -0.03] respectively)., Conclusions: In metabolically well-controlled patients with DM2, ALT levels are related to decreased insulin-sensitivity and an impaired conduit vessel vascular function.

We investigated the effects of aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril on urinary albumin excretion, endothelial function and inflammatory activity in hypertensive type II diabetic individuals. A total of 70 hypertensive type II diabetic individuals were treated with three antihypertensive strategies in a randomized, double-blind, double-dummy design. Blood pressure was titrated to levels below 130/85 mmHg or a decrease in systolic pressure of 10% with a diastolic pressure below 85 mmHg. After titration, patients were treated for 12 months. Mean blood pressures changed from 157/93, 151/94 and 149/93 at baseline to 135/80, 135/82 and 131/80 mmHg after titration in the hydrochlorothiazide (n=24), candesartan (n=24) and lisinopril (n=22) groups. About 70% reached target blood pressures. However, only 45% had blood pressures <130/85 mmHg. Urinary albumin excretion and levels of soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 decreased (GEE regression coefficients, -2.40 mg/24 h (P<0.001), -85 ng/ml (P=0.01) and -50 ng/ml (P=0.02)), but brachial artery endothelium-dependent and -independent vasodilation and levels of von Willebrand factor and C-reactive protein did not change (GEE regression coefficients, 0.21 mm (P=0.07), 0.04 mm (P=0.43), 0.04 IU/ml (P=0.33) and -1.15 mg/l (P=0.64)). No differences in outcome variables between treatment groups were observed. These data show that achievement of target blood pressures below 130/85 mmHg in hypertensive type II diabetes is difficult. Aggressive antihypertensive therapy can improve urinary albumin excretion, endothelial function and inflammatory activity in hypertensive type II diabetic individuals, regardless of the type of antihypertensive therapy used.

Impaired glucose metabolism (IGM) and type 2 diabetes (DM-2) are associated with high cardiovascular disease risk. Increases in peripheral and central artery stiffness may represent pathophysiologic pathways through which glucose tolerance status leads to cardiovascular disease. Peripheral artery stiffness increases with deteriorating glucose tolerance status, whereas this trend remains unclear for central artery stiffness. Therefore, we investigated the associations between glucose tolerance status and estimates of central arterial stiffness. We performed a population-based study of 619 individuals (normal glucose metabolism, n=261; IGM, n=170; and DM-2, n=188) and assessed central artery stiffness by measuring total systemic arterial compliance, aortic pressure augmentation index, and carotid-femoral transit time. After adjustment for sex, age, heart rate, height, body mass index, and mean arterial pressure, DM-2 was associated with decreased total systemic arterial compliance, increased aortic augmentation index, and decreased carotid-femoral transit time. IGM was borderline significantly associated with decreased total systemic arterial compliance. Respective regression coefficients (95% confidence intervals) for IGM and DM-2 compared with normal glucose metabolism were -0.05 (-0.11 to 0.01) and -0.13 (-0.19 to -0.07) mL/mm Hg for total systemic arterial compliance; 1.1 (-0.2 to 2.5) and 1.6 (0.2 to 3.0) percentage points for aortic augmentation index; and -0.85 (-5.20 to 3.49) and -4.95 (-9.41 to -0.48) ms for carotid-femoral transit time. IGM and DM-2 are associated with increased central artery stiffness, which is more pronounced in DM-2. Deteriorating glucose tolerance is associated with increased central and peripheral arterial stiffness, which may partly explain why both DM-2 and IGM are associated with increased cardiovascular risk.

This randomised double-blind, placebo-controlled, clinical trial investigated the effect of 3 months of treatment with calcium dobesilate on endothelium-dependent vasodilation, markers of endothelial function, blood pressure, and markers of oxidation in obese, male smokers. Vascular effects may depend on the type of vessel and we, therefore, investigated both smaller arteries, i.e. resistance arteries and small arterioles, and large conduit arteries. Vascular function was measured by acetylcholine- and sodium-nitroprusside-mediated vasodilation, and capillary recruitment, in the skin microcirculation; by forearm blood flow (FBF) responses to several agonists and to N-G-monomethyl L-arginine (L-NMMA) in the forearm vascular bed; by flow-mediated vasodilation in the brachial artery; and by determination of soluble levels of vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1) and E-selectin. Twenty-eight individuals received dobesilate and 24 placebo. No effect of calcium dobesilate on endothelial function, blood pressure or markers of oxidation was observed compared with placebo. The difference in acetylcholine-mediated vasodilation in the microcirculation was -52.1%-point (95% confidence interval -132.8 to 28.1); in sodium-nitroprusside-mediated vasodilation in the microcirculation, 2.6%-point (-95.1 to 100.2); in capillary recruitment, 2.5%-point (-6.8 to 11.7); in acetylcholine-induced increases in FBF (n=28), 23%-point (-173 to 126); in L-NMMA-induced reduction of basal FBF, -2.8%-point (-29.3 to 23.8); in flow-mediated vasodilation of the brachial artery, 0.3%-points (-2.7 to 3.3); in 24-h systolic blood pressure, 2.1 mmHg (-1.3 to 5.5); in soluble VCAM-1, 54 ng/ml (-8 to 115); in soluble ICAM-1, 9 ng/ml (-49 to 67); in sE-selectin, -17 ng/ml (-44 to 11); in ketocholesterol 5 nM (-17 to 26); and in oxidised LDL -1.6 U/l (-6.7 to 3.5). We have shown that endothelial function, blood pressure, and markers of oxidation were not affected by 3 months of treatment with calcium dobesilate in mildly obese, smoking men. Thus, our data provide no evidence of an effect on vascular function of calcium dobesilate in humans.

Background: Type 2 diabetes mellitus is associated with an increased risk of atherothrombotic disease, which may in part be mediated through increased arterial stiffness. We investigated to what extent increased arterial stiffness is associated with cardiovascular risk factors that commonly cluster in type 2 diabetes., Design: In this cross-sectional, observational study we assessed, in 81 subjects with type 2 diabetes, local distensibility and compliance of the common carotid and femoral arteries, and carotido-femoral transit time. We subsequently investigated whether these measures of arterial stiffness were determined by diabetes duration, blood pressure, lipid levels (including fasting and postprandial triglyceridaemia), hyperglycaemia, BMI, waist-to-hip ratio, insulin resistance (as measured by a euglycaemic, hyperinsulinaemic clamp), hyperinsulinaemia, cigarette smoking, or the use of alcohol., Results: In multivariate analysis, insulin-mediated glucose uptake was positively [standardized beta, 0.21 (P = 0.05)] associated with the carotid artery compliance coefficient, and the use of alcohol was negatively associated with the femoral artery compliance coefficient [standardized beta, -0.25 (P = 0.03)]. Except for mean arterial pressure, which was negatively associated with all outcome variables, the other cardiovascular risk factors that we investigated were not significantly associated with the distensibility coefficients of both the carotid and femoral artery, or with the carotido-femoral transit time., Conclusions: In subjects with type 2 diabetes mellitus, insulin resistance and the use of alcohol were associated with increased arterial stiffness, which supports the hypothesis that increased arterial stiffness can act as a mediating factor in the association between type 2 diabetes mellitus and increased risk of atherothrombotic disease. We found no evidence for an association between fasting or postprandial triglyceridaemia and arterial stiffness.

Objective: Type 2 diabetic patients have an increased arterial stiffness and a very high risk of cardiovascular death. The present study investigated the relationship between pulse pressure, an indicator of vascular stiffness, and risk of cardiovascular mortality among type 2 diabetic and non-diabetic individuals. Second, we determined the relationship between pulse pressure and its main determinant (i.e. age), and the influence of diabetes and mean arterial pressure on this relationship., Design and Methods: We studied a cohort of 2484 individuals including 208 type 2 diabetic patients. Mean age and median follow-up for non-diabetic and diabetic individuals, respectively, were 61 and 66 years, and 8.8 and 8.6 years. One-hundred and sixteen non-diabetic and 34 diabetic individuals died of cardiovascular causes. Relative risks of cardiovascular mortality were estimated by Cox proportional hazards regression adjusted for age, gender and mean arterial pressure., Results: Pulse pressure was associated with cardiovascular mortality among the diabetic, but not among the non-diabetic individuals [adjusted relative risk (95% confidence interval) per 10 mmHg increase, 1.27 (1.00-1.61) and 0.98 (0.85-1.13), P interaction = 0.07]. Further adjustment for other risk factors gave similar results. The association, at baseline, between age and pulse pressure was dependent on the presence of diabetes (P interaction = 0.03) and on the mean arterial pressure (P interaction< 0.001) (i.e. there was a stronger association when diabetes was present and when mean arterial pressure was higher)., Conclusions: We conclude that, in type 2 diabetes, pulse pressure is positively associated with cardiovascular mortality. The association between age and pulse pressure is influenced by the presence of type 2 diabetes and by the height of the mean arterial pressure. These findings support the concept of accelerated vascular aging in type 2 diabetes.

Brachial artery pulse pressure is a predictor of (cardiovascular) morbidity, but its determinants in individuals with Type II diabetes and untreated mild hypertension have not been elucidated. We therefore cross-sectionally investigated determinants of brachial artery mean 24 h pulse pressure in 60 individuals (40 males; age, mean +/- S.D., 57.8 +/- 7.5 years) with Type II diabetes [median diabetes duration (interquartile range), 6.3 (3.6-10.1) years] and untreated mild hypertension [sitting blood pressure >140/90 mmHg and <190/120 mmHg (mean of two consecutive auscultatory office measurements after 5 min of rest)]. We measured (1) three potential determinants reflecting different aspects of central artery stiffness [the overall systemic arterial compliance, the aortic augmentation index and 1/(regional carotido-femoral transit time)], (2) structural and functional changes of the circulatory system often observed in Type II diabetes, and (3) diabetes-associated metabolic variables. After adjustment for age, gender and mean arterial pressure, brachial artery pulse pressure was associated with autonomic function [standardized regression coefficient (beta), -0.27 (P=0.01)], blood pressure decline during sleep [standardized beta, -0.32 (P=0.002)], fasting glucose concentration [standardized beta, 0.26 (P=0.01)], HbA(1c) concentration [standardized beta, 0.27 (P=0.003)] and diabetes duration [standardized beta, 0.28 (P=0.002)] in linear regression analyses. In a combined multivariate model, brachial artery pulse pressure was independently determined by gender [1=male, 2=female; standardized beta, 0.24 (P=0.01)], diabetes duration [standardized beta, 0.18 (P=0.03)], mean arterial pressure [standardized beta, 0.32 (P=0.002)], systemic arterial compliance [standardized beta, -0.23 (P=0.02)] and fasting glucose concentration [standardized beta, 0.20 (P=0.02)]. Aortic augmentation index and 1/(carotido-femoral transit time) were not independently associated with pulse pressure. In conclusion, in individuals with Type II diabetes and untreated mild hypertension, brachial artery pulse pressure is determined mainly by proximal aortic stiffness in a way which is not strongly influenced by peripheral pulse wave reflection. Approx. 60% of the variance in brachial artery pulse pressure could be explained by potentially modifiable determinants.

Homocysteine is associated with atherothrombotic disease, which may be mediated through associations of homocysteine levels with blood pressure, endothelial function, or arterial stiffness. In a placebo-controlled, randomized clinical trial, we measured blood pressure, brachial artery endothelium-dependent vasodilation, and common carotid artery stiffness in 158 clinically healthy siblings of patients with premature atherothrombotic disease at baseline and after 1 and 2 years of homocysteine-lowering treatment with folic acid (5 mg) plus pyridoxine (250 mg). Intention-to-treat analyses limited to participants (n=130) who underwent at least 1 measurement after the baseline visit showed that compared with placebo, treatment with folic acid plus pyridoxine was associated with a 3.7-mm Hg (95% CI -6.8 to -0.6 mm Hg) lower systolic and a 1.9-mm Hg (95% CI -3.7 to -0.02 mm Hg) lower diastolic blood pressure over the 2-year trial period. Together with the decreased occurrence of abnormal exercise electrocardiography tests reported previously, our results support the hypothesis that homocysteine-lowering treatment with folic acid plus pyridoxine has beneficial vascular effects. Because no effects could be demonstrated on brachial artery endothelium-dependent vasodilation or on common carotid artery stiffness, the present study does not support the hypothesis that the cardiovascular effects of homocysteine are mediated through these factors, at least in clinically healthy individuals.

Background: Decreased large artery function, as reflected by increased brachial artery pulse pressure and increased carotid artery diameter and stiffness, may contribute to the increased mortality risk that is observed in subjects with impaired glucose tolerance. We therefore investigated the association between brachial artery pulse pressure and carotid artery diameter and stiffness, which are estimates of central artery stiffness and arterial remodelling, respectively, and mortality in subjects with a recent history of impaired glucose tolerance., Design: A prospective, population-based cohort study. We measured brachial artery pulse pressure by oscillometric blood pressure measurements, and common carotid artery diameter and distensibility and compliance coefficients by ultrasound in 140 subjects with a recent history of impaired glucose tolerance. During a median 6.6-year follow-up, 16 subjects died., Results: Brachial artery pulse pressure and common carotid artery diameter were positively related to all-cause mortality [hazard ratios per standard deviation, 1.7 (1.2-2.5) and 2.1 (1.3-3.3), respectively]. Results were similar after adjustment for gender, age, waist-to-hip ratio, body mass index, total cholesterol concentration, pre-existent cardiovascular disease, and hypertension, and after additional mutual adjustment. Common carotid artery distensibility and compliance coefficients were not statistically significantly associated with mortality., Conclusions: Among subjects with a recent history of impaired glucose tolerance, brachial artery pulse pressure and common carotid artery diameter are independently associated with mortality risk. Stiffness of the central arteries may explain the association between pulse pressure and mortality risk. The association between carotid diameter and mortality risk is more likely to reflect arterial remodelling in response to atherosclerosis than that in response to increased local stiffness.

Complications arising from otitis media are rare. However, it is still important to be aware of the potential complications of the infection. Two patients with petrositis who developed Gradenigo's triad (otitis, abducens paralysis and pain) are presented.