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INTRODUCTION: The spatial and temporal patterns of cortical mean diffusivity (cMD), as well as its association with Alzheimer's disease (AD) and suspected non‐Alzheimer's pathophysiology (SNAP), are not yet fully understood. METHODS: We compared baseline (n = 617) and longitudinal changes (n = 421) of cMD, cortical thickness, and gray matter volume and their relations to vascular risk factors, amyloid beta (Aβ), and tau positron emission tomography (PET), and longitudinal cognitive decline in Aβ PET negative and positive older adults. RESULTS: cMD increases were more sensitive to detecting brain structural alterations than cortical thinning and gray matter atrophy. Tau‐related cMD increases partially mediated Aβ‐related cognitive decline in AD, whereas vascular disease‐related increased cMD levels substantially mediated age‐related cognitive decline in SNAP. DISCUSSION: These findings revealed the dynamic changes of microstructural and macrostructural indicators and their associations with AD and SNAP, providing novel insights into understanding upstream and downstream events of cMD in neurodegenerative disease. Highlights: Cortical mean diffusivity (cMD) was more sensitive to detecting structural changes than macrostructural factors.Tau‐related cMD increases partially mediated amyloid beta–related cognitive decline in Alzheimer's disease (AD).White matter hyperintensity–related higher cMD mainly explained the age‐related cognitive decline in suspected non‐Alzheimer's pathophysiology (SNAP).cMD may assist in tracking earlier neurodegenerative signs in AD and SNAP. [ABSTRACT FROM AUTHOR]

Vasculogenic erectile dysfunction (ED) is the most common form of ED affecting the male population. Once the first line investigation for erectile dysfunction, penile Doppler ultrasound examinations have reduced in number following the introduction of oral phosphodiesterase inhibitors as a treatment method. As such, skilled professionals versed in the performance of these examinations are dwindling. This skill deficit is compounded by the lack of standardisation that exists in the performance and interpretation of penile haemodynamics relative to impotence of vascular origin. Despite the success of pharmacological agents in the treatment of vasculogenic dysfunction, penile Doppler examinations are still relevant in the assessment of ED in non‐responders, and those patients in which pelvic surgery or trauma has altered the normal erectile mechanism. Growing evidence in the literature also suggests that vasculogenic ED may be an early indicator of systemic vascular disease and therefore prognostic of future cardiovascular events. Considering this, the relevance of Doppler assessment of penile haemodynamics with ultrasound should not be underestimated. This article will introduce the sonographer to advanced vascular anatomy of the penis, pathophysiology of erectile function and the principles of normal and pathological penile haemodynamic patterns. It also aims to suggest a standardised protocol for the performance of penile Doppler ultrasound relative to primary vasculogenic ED and reduce the amount of variability that exits between operators. As such the sonographer can make a significant contribution to patient management pathways. [ABSTRACT FROM AUTHOR]

The discovery of driver mutations in myeloproliferative neoplasms has significantly contributed to the management of patients with essential thrombocythaemia (ET). High‐quality evidence has started to pave the way for targeted therapy. The review by Ferrer‐Marín et al. further advances this discussion, highlighting how molecular profiling, including non‐driver gene mutations, is set to revolutionize personalized treatment approaches for ET patients. Commentary on: Ferrer‐Marín et al. Essential thrombocythemia: a contemporary approach with new drugs on the horizon. Br J Haematol 2024;204:1605‐1616. [ABSTRACT FROM AUTHOR]

Verticillium longisporum is a soilborne fungal vascular pathogen of Brassica crops. Three hybrid lineages originating from three independent hybridization events of four haploid Verticillium parents are known. V. longisporum lineage A1/D2 has only been found in horseradish and previous pathogenicity tests have shown that it is non‐aggressive on oilseed rape (Brassica napus). The aim of this study was to investigate the interaction of the non‐aggressive lineage A1/D2 with oilseed rape in comparison with the aggressive A1/D1 lineage. Although A1/D2 did not cause severe disease symptoms, the study revealed restricted root infection and systemic colonization by this lineage, as assessed by quantitative PCR of fungal DNA. Assessment of root surface colonization by confocal laser microscopy indicated early sporulation, disorganized loosely attached hyphal growth and hyphal coiling of A1/D2. By contrast, A1/D1 showed organized hyphal growth tight to the root surface, as well as hyphal swellings at points of penetration. Vascular colonization was studied with transmission electron microscopy, which revealed less vessel colonization, higher intensity of vascular responses and lower plant cell wall degradation in A1/D2‐treated plants in comparison with A1/D1. Vascular responses consisted of strong coating of vessel walls and fungal hyphae with an electron‐dense material, indicating higher intensity of plant defence in comparison with A1/D1. The results, for the first time, demonstrate stem colonization and thus a basic level of pathogenic interaction of non‐aggressive strains of A1/D2 with oilseed rape associated with a lack of severe disease symptoms, which indicate tolerance in oilseed rape to lineage A1/D2. [ABSTRACT FROM AUTHOR]

Pseudoaneurysms are frequent vascular anomalies. This review article aims to describe the unique specific aspect of pseudoaneurysm (PSA) that allows to make the diagnosis using different modalities: colour Doppler ultrasound, computed tomographic angiography, magnetic resonance angiography and conventional angiography. It is essential to know the various aetiologies of PSA: iatrogenic, traumatic, dissecting and anastomotic; different locations and the possible complications, information to help clinicians choose the best treatment. Our review is supported by illustrated series of cases. [ABSTRACT FROM AUTHOR]

Introduction: Dementia prediction models are necessary to inform the development of dementia risk reduction strategies. Here, we examine the utility of neuropathological‐based risk scores to predict clinical dementia. Methods: Models were developed for predicting Alzheimer's disease (AD) and non‐AD neuropathologies using the Honolulu Asia Aging neuropathological sub‐study (HAAS; n = 852). Model accuracy for predicting clinical dementia, over 30 years, was tested in the non‐autopsied HAAS sample (n = 2960) and the Age, Gene/Environment Susceptibility‐Reykjavik Study (n = 4614). Results: Different models were identified for predicting neurodegenerative and vascular neuropathology (c‐statistic range: 0.62 to 0.72). These typically included age, APOE, and a blood pressure‐related measure. The neurofibrillary tangle and micro‐vascular lesion models showed good accuracy for predicting clinical vascular dementia. Discussion: There may be shared risk factors across dementia‐related lesions, suggesting common pathways. Strategies targeting these models may reduce risk or postpone clinical symptoms of dementia as well as reduce neuropathological burden associated with AD and vascular lesions. [ABSTRACT FROM AUTHOR]

Since the 1960s, several drugs have been linked to the onset or aggravation of pulmonary arterial hypertension (PAH): dasatinib, some amphetamine‐like appetite suppressants (aminorex, fenfluramine, dexfenfluramine, benfluorex) and recreational drugs (methamphetamine). Moreover, in numerous cases, the implication of other drugs with PAH have been suggested, but the precise identification of iatrogenic aetiologies of PAH is challenging given the scarcity of this disease and the potential long latency period between drug intake and PAH onset. In this context, we used the World Health Organization's pharmacovigilance database, VigiBase, to generate new hypotheses about drug associated PAH. Methods: We used VigiBase, the largest pharmacovigilance database worldwide to generate disproportionality signals through the Bayesian neural network method. All disproportionality signals were further independently reviewed by experts in pulmonary arterial hypertension, pharmacovigilance and vascular pharmacology and their plausibility ranked according to World Health Organization causality categories. Results: We included 2184 idiopathic PAH cases, yielding a total of 93 disproportionality signals. Among them, 25 signals were considered very likely, 15 probable, 28 possible and 25 unlikely. Notably, we identified 4 new protein kinases inhibitors (lapatinib, lorlatinib, ponatinib and ruxolitinib), 1 angiogenesis inhibitor (bevacizumab), and several chemotherapeutics (etoposide, trastuzumab), antimetabolites (cytarabine, fludarabine, fluorouracil, gemcitabine) and immunosuppressants (leflunomide, thalidomide, ciclosporin). Conclusion: Such signals represent plausible adverse drug reactions considering the knowledge of iatrogenic PAH, the drugs' biological and pharmacological activity and the characteristics of the reported case. Although confirmatory studies need to be performed, the signals identified may help clinicians envisage an iatrogenic aetiology when faced with a patient who develops PAH. [ABSTRACT FROM AUTHOR]

We studied small vessel disease (SVD) pathology in Familial Alzheimer's disease (FAD) subjects carrying the presenilin 1 (PSEN1) p.Glu280Ala mutation in comparison to those with sporadic Alzheimer's disease (SAD) as a positive control for Alzheimer's pathology and Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) bearing different NOTCH3 mutations, as positive controls for SVD pathology. Upon magnetic resonance imaging (MRI) in life, some FAD showed mild white matter hyperintensities and no further radiologic evidence of SVD. In post‐mortem studies, total SVD pathology in cortical areas and basal ganglia was similar in PSEN1 FAD and CADASIL subjects, except for the feature of arteriosclerosis which was higher in CADASIL subjects than in PSEN1 FAD subjects. Further only a few SAD subjects showed a similar degree of SVD pathology as observed in CADASIL. Furthermore, we found significantly enlarged perivascular spaces in vessels devoid of cerebral amyloid angiopathy in FAD compared with SAD and CADASIL subjects. As expected, there was greater fibrinogen‐positive perivascular reactivity in CADASIL but similar reactivity in PSEN1 FAD and SAD groups. Fibrinogen immunoreactivity correlated with onset age in the PSEN1 FAD cases, suggesting increased vascular permeability may contribute to cognitive decline. Additionally, we found reduced perivascular expression of PDGFRβ AQP4 in microvessels with enlarged PVS in PSEN1 FAD cases. We demonstrate that there is Aβ‐independent SVD pathology in PSEN1 FAD, that was marginally lower than that in CADASIL subjects although not evident by MRI. These observations suggest presence of covert SVD even in PSEN1, contributing to disease progression. As is the case in SAD, these consequences may be preventable by early recognition and actively controlling vascular disease risk, even in familial forms of dementia. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of livedoid vasculopathy (LV) remains unknown. Although platelet activation occurs in LV, little research has been conducted on LV platelet morphology parameters. The purpose of this study was to investigate whether platelet morphology changes in LV and its clinical significance. Methods: Twenty‐seven LV patients and 21 cutaneous small vessel vasculitis (CSVV) patients, all at the active stage, were included. Platelet parameters in active‐ and stable‐stage LV and CSVV patients were compared. Correlations between these platelet parameters and LV composite clinical scores were analysed. Results: LV patients' mean age was 25.48 years (range: 9–62 years), and 81.48% (22/27) were women and 18.52% (5/27) were men. The platelet counts and plateletcrit (PCT) levels were significantly elevated in LV patients compared with CSVV patients and in active‐stage LV patients compared with stable‐stage LV patients after treatment. LV patient composite clinical scores that reflected disease severity and activity were positively correlated with the platelet count and PCT levels. Conclusion: Altered platelet morphology was detected in LV patients. Platelet count and PCT might be haematological biomarkers for early prediction of LV activity and relapses and for differential identification between LV and CSVV. [ABSTRACT FROM AUTHOR]

Autophagy is an essential intracellular process for cellular quality control. It enables cell homeostasis through the selective degradation of harmful protein aggregates and damaged organelles. Autophagy is essential for recycling nutrients, generating energy to maintain cell viability in most tissues and during adverse conditions such as hypoxia/ischaemia. The progressive understanding of the mechanisms modulating autophagy in the vasculature has recently led numerous studies to link intact autophagic responses with endothelial cell (EC) homeostasis and function. Preserved autophagic flux within the ECs has an essential role in maintaining their physiological characteristics, whereas defective autophagy can promote endothelial pro‐inflammatory and atherogenic phenotype. However, we still lack a good knowledge of the complete molecular repertoire controlling various aspects of endothelial autophagy and how this is associated with vascular diseases. Here, we provide an overview of the current state of the art of autophagy in ECs. We review the discoveries that have so far defined autophagy as an essential mechanism in vascular biology and analyse how autophagy influences ECs behaviour in vascular disease. Finally, we emphasise opportunities for compounds to regulate autophagy in ECs and discuss the challenges of exploiting them to resolve vascular disease. [ABSTRACT FROM AUTHOR]

Background: The key goals of management in patients with type 2 diabetes (T2D) are to prolong life and improve quality of life. Micro‐ and macrovascular complications of T2D not only increase the risk of morbidity and mortality, but cross‐sectional studies indicate they may also worsen quality of life. We prospectively examined the association of complications that developed during the follow‐up with concurrent changes in quality of life. Materials and methods: DISCOVER is a multinational, prospective, observational cohort study of T2D patients enrolled at initiation of second‐line glucose‐lowering therapy. Quality of life was assessed with the SF‐36 Physical (PCS) and Mental Components Summary (MCS) scores at baseline, 6 months, and 1, 2 and 3 years. Hierarchical repeated measures regression models for PCS and MCS were constructed with complications included as time‐dependent covariates; first each complication was modelled alone and then second including all interval complications (to account for different complications occurring in the same patient). Results: Among 7830 patients with T2D from 30 countries (mean age 56.6 years, 47.6% women, mean duration of T2D 5.6 years), baseline mean SF‐36 PCS was 48.0 ± 7.8 and SF‐36 MCS was 45.5 ± 10.4. At baseline, 1422 (18.2%) patients had a known microvascular complication, and 966 (12.3%) had a macrovascular complication. Over the 3 years of the study, 641 (12.0%) developed a new microvascular complication (most commonly neuropathy) and 372 (5.8%) developed a new macrovascular complication (most commonly coronary disease). New diagnoses of coronary disease, peripheral artery disease, heart failure and neuropathy were each associated with subsequent moderate reductions in SF‐36 PCS (range 0.7 to 1.6 points) and new cerebrovascular disease was associated with a reduction in SF‐36 MCS (2.6 points). Results were consistent when all interval complications were considered in the same model. Conclusion: In a prospective, multinational study of patients with T2D, the development of macrovascular complications and neuropathy was associated with decreases in both physical and mental quality of life. Our results provide additional support for clinicians to focus on the prevention, detection and management of the complications of T2D. [ABSTRACT FROM AUTHOR]

Background: Despite improved surgical approaches for chronic limb‐threatening ischemia (CLTI), amputation rates remain high and contributing tissue‐level factors remain unknown. The purpose of this study was twofold: (1) to identify differences between the healthy adult and CLTI limb muscle proteome, and (2) to identify differences in the limb muscle proteome of CLTI patients prior to surgical intervention or at the time of amputation. Methods and results: Gastrocnemius muscle was collected from non‐ischemic controls (n = 19) and either pre‐interventional surgery (n = 10) or at amputation outcome (n = 29) CLTI patients. All samples were subjected to isobaric tandem‐mass‐tag‐assisted proteomics. The mitochondrion was the primary classification of downregulated proteins (> 70%) in CLTI limb muscles and paralleled robust functional mitochondrial impairment. Upregulated proteins (> 38%) were largely from the extracellular matrix. Across the two independent sites, 39 proteins were downregulated and 12 upregulated uniformly. Pre‐interventional CLTI muscles revealed a robust upregulation of mitochondrial proteins but modest functional impairments in fatty acid oxidation as compared with controls. Comparison of pre‐intervention and amputation CLTI limb muscles revealed mitochondrial proteome and functional deficits similar to that between amputation and non‐ischemic controls. Interestingly, these observed changes occurred despite 62% of the amputation CLTI patients having undergone a prior surgical intervention. Conclusions: The CLTI proteome supports failing mitochondria as a phenotype that is unique to amputation outcomes. The signature of pre‐intervention CLTI muscle reveals stable mitochondrial protein abundance that is insufficient to uniformly prevent functional impairments. Taken together, these findings support the need for future longitudinal investigations aimed to determine whether mitochondrial failure is causally involved in amputation outcomes from CLTI. [ABSTRACT FROM AUTHOR]

Background: High blood pressure (BP) is a common risk factor for cerebral small vessel disease including white matter hyperintensity (WMH). Whether increased BP exacerbates WMH by impacting cerebral vascular morphologies remains poorly studied. Purpose: To determine the relationships among high BP, cerebrovascular morphologies, and WMH in elderly individuals. Study Type: Cohort. Subjects: Eight hundred sixty‐three participants (54.2% female) from the Taizhou Imaging Study without clinical evidence of neurologic disorders were included in the analyses. Field Strength/Sequence: 3.0 T; time‐of‐flight magnetic resonance angiography (TOF MRA); T2 fluid‐attenuated inversion recovery (FLAIR); T1 magnetization‐prepared rapid gradient‐echo; gradient echo T2*‐weighted; diffusion tensor imaging; pulsed arterial spin labeling. Assessment: Cerebrovascular morphologic measurements were quantified based on the TOF MRA images, including vessel density, radius, tortuosity, and branch number. WMH lesion volumes (WMHV) and WMH lesion counts (WMHC) were calculated automatically based on the T2 FLAIR images. Statistical Tests: Multivariable linear regression analysis and path analysis with a linear single‐mediator model were employed. A P value <0.05 was considered statistically significant. Results: Higher BP, especially diastolic BP, was significantly correlated with lower cerebrovascular density (β = −104) and lower branch numbers (β = −0.02). Although decreased tortuosity (β = −1.25) and increased radius (β = 93.8) were correlated with BP, no significant relationship of tortuosity (β = −4.6 × 10−4, P = 0.58) or radius (β = 0.03, P = 0.08) with BP in small vessels was found. The proportion of small vessels decreased as BP increased (SBP: β = −6.6 × 10−4; DBP: β = −9.0 × 10−4). Similarly, increased WMHV and WMHC were associated with decreased vessel density (volumes: β = −24, counts: β = −127), decreased tortuosity (volumes: β = −0.08, counts: β = −0.53), and increased radius (volumes: β = 12.6, counts: β = 86.6). Path analyses suggested an association between high BP and WMHs that were mediated by cerebrovascular morphologic changes. Data Conclusion: Structural alterations of cerebral vessels induced by high BP are correlated with WMH. This result suggested that elevated BP might be one of the pathophysiological mechanisms involving in the co‐occurrence of cerebrovascular alteration and small vessel disease. Level of Evidence: 1 Technical Efficacy Stage: 1 [ABSTRACT FROM AUTHOR]

Livedoid vasculopathy (LV) is considered a disease of hypercoagulability. Association of LV with genetic variants is poorly characterised and large‐scale genetic association studies have not been performed. The aim of the study was to systematically review variants in LV patients and to analyse the available clinical data. A systematic search of the literature in PubMed and Embase databases was performed to identify articles investigating genetic variation in LV patients. Thirty studies or case reports were identified that reported 265 LV patients tested for at least one out of six genetic variations. Among them, PAI‐1 ‐675 4G/5G was the most common, accounting for 85.26% (81/95). Heterozygous 4G/5G was the major genotype. PAI‐1 A844G, MTHFR C677T, and MTHFR A1298C were the second, third, and fourth most common variants in LV patients. Prothrombin G20210A and Factor V G1691A were mainly present in LV patients from Europe, North America, and South America. This review highlights the associations between LV and genetic variants. The distribution of variants may be geographically or ethnicity dependent; however, large sample case‐control studies are needed to clarify associations. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysm (AAA) is a vascular disease found to have progressive growth in the area of aorta. Rupturing of aorta causes excessive bleeding that leads to health‐related issues, which can be fatal sometimes. Therefore, it becomes important to make early diagnosis of AAA and its condition and start immediate treatment. Blood‐based biomarker helps to diagnose AAA and to monitor the condition after AAA surgery. N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) is a hormone produced in the heart in small quantities and increased when the heart needs to work harder. NT‐proBNP was proved to be strongly linked with AAA incidence. Moreover, quantifying the level of NT‐proBNP helps to determine the risk factors on cardiovascular system after the surgery. This work is quantifying the NT‐proBNP on interdigitated electrode sensor by using NT‐proBNP binding aptamer. The detection limit of NT‐proBNP was calculated as 1 pg/mL on a linear regression curve [y = 0.2148x + 0.8849; R² = 0.9049]. The linear range with dose‐dependent analysis was from 0.01 until 100 ng/mL. Moreover, the control experiment with complementary aptamer sequence did not show the current signal, specifying the detection of NT‐proBNP. This research benefits to identify the heart condition of patient after the removal of AAA. [ABSTRACT FROM AUTHOR]

Background and purpose: Elevated serum matrix metalloproteinase‐8 (MMP‐8) concentrations are associated with high risk of vascular disease, but the causality remains unclear. A two‐sample Mendelian randomization (MR) study was performed to examine the causal effect of serum MMP‐8 concentrations on the risk of ischaemic stroke, ischaemic stroke subtypes and coronary artery disease. Methods: Ten independent single‐nucleotide polymorphisms related to serum MMP‐8 concentrations were identified as instrumental variables from a genome‐wide association study of 6049 European subjects. Genetic association estimates for ischaemic stroke were obtained from the Multiancestry Genome‐wide Association Study of Stroke consortium with 446,696 European individuals. The inverse‐variance weighted method was applied to assess the causal associations of serum MMP‐8 with ischaemic stroke and its subtypes in the main analysis. Results: No significant causal association was observed for MMP‐8 levels with total ischaemic stroke, large artery stroke or cardioembolic stroke. Genetically determined 1 – unit higher log‐transformed serum MMP‐8 concentration was associated with an increased risk of small vessel stroke (odds ratio 1.25; 95% confidence interval 1.12–1.39; p < 0.001). In secondary analysis, a similar adverse impact was reported for MMP‐8 on coronary artery disease (odds ratio 1.05; 95% confidence interval 1.01–1.10; p = 0.017). Sensitivity analyses further confirmed the relationship between serum MMP‐8 level and small vessel stroke and coronary artery disease. Mendelian randomization Egger regression showed no evidence of pleiotropic bias. Conclusions: High serum MMP‐8 concentrations were causally associated with increased risks of small vessel stroke and coronary artery disease. The mechanism underlying the effect of serum MMP‐8 on the vascular system requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Phosphorylcholine (PC) is an important pro‐inflammatory damage‐associated molecular pattern. Previous data have shown that natural IgM anti‐PC protects against cardiovascular disease. We aimed to develop a monoclonal PC IgG antibody with anti‐inflammatory and anti‐atherosclerotic properties. Methods: Using various techniques PC antibodies were validated and optimized. In vivo testing was performed in a femoral artery cuff model in ApoE3*Leiden mice. Safety studies are performed in rats and cynomolgus monkeys. Results: A chimeric anti‐PC (PC‐mAb(T15), consisting of a human IgG1 Fc and a mouse T15/E06 Fab) was produced, and this was shown to bind specifically to epitopes in human atherosclerotic tissues. The cuff model results in rapid induction of inflammatory genes and altered expression of genes associated with ER stress and choline metabolism in the lesions. Treatment with PC‐mAb(T15) reduced accelerated atherosclerosis via reduced expression of endoplasmic reticulum stress markers and CCL2 production. Recombinant anti‐PC Fab fragments were identified by phage display and cloned into fully human IgG1 backbones creating a human monoclonal IgG1 anti‐PC (PC‐mAbs) that specifically bind PC, apoptotic cells and oxLDL. Based on preventing macrophage oxLDL uptake and CCL2 production, four monoclonal PC‐mAbs were selected, which to various extent reduced vascular inflammation and lesion development. Additional optimization and validation of two PC‐mAb antibodies resulted in selection of PC‐mAb X19‐A05, which inhibited accelerated atherosclerosis. Clinical grade production of this antibody (ATH3G10) significantly attenuated vascular inflammation and accelerated atherosclerosis and was tolerated in safety studies in rats and cynomolgus monkeys. Conclusions: Chimeric anti‐PCs can prevent accelerated atherosclerosis by inhibiting vascular inflammation directly and through reduced macrophage oxLDL uptake resulting in decreased lesions. PC‐mAb represents a novel strategy for cardiovascular disease prevention. [ABSTRACT FROM AUTHOR]

Keywords: gestational diabetes; heart disease; primary prevention; type 2 diabetes mellitus; vascular disease EN gestational diabetes heart disease primary prevention type 2 diabetes mellitus vascular disease 1 5 5 07/12/21 20210701 NES 210701 Gestational diabetes (GDM) is one of the most common complications of pregnancy worldwide, with 5% to 20% of newborns being offspring of mothers with GDM.1 SP , sp 2 In addition to the impact of GDM on pregnancy care and outcomes,3 SP , sp 4 it has become evident that GDM affects women well beyond delivery. Follow-up of women with a history of gestational diabetes in Italy: Are we missing an opportunity for primary prevention of type 2 diabetes and cardiovascular disease? Indeed, women with a history of GDM have an increased risk of being diagnosed with type 2 diabetes mellitus post-partum or later in their life, as well as an increased susceptibility to cardiovascular disease (CVD).5 SP , sp 6 The increased risk of type 2 diabetes among women with a history of GDM was recognized long time ago. 2014; 14 (1): 41. 23 Bernstein JA, McCloskey L, Gebel CM, Iverson RE, Lee-Parritz A. Lost opportunities to prevent early onset type 2 diabetes mellitus after a pregnancy complicated by gestational diabetes. [Extracted from the article]

Sepsis represents one of the major medical challenges of the 21st century. Despite substantial improvements in the knowledge on pathophysiological mechanisms, this has so far not translated into novel adjuvant treatment strategies for sepsis. In sepsis, both vascular tone and vascular integrity are compromised, and contribute to the development of shock, which is strongly related to the development of organ dysfunction and mortality. In this review, we focus on dipeptidyl peptidase 3 (DPP3) and adrenomedullin (ADM), two molecules that act on the vasculature and are involved in the pathophysiology of sepsis and septic shock. DPP3 is an ubiquitous cytosolic enzyme involved in the degradation of several important signalling molecules essential for regulation of vascular tone, including angiotensin II. ADM is a key hormone involved in the regulation of vascular tone and endothelial barrier function. Previous studies have shown that circulating concentrations of both DPP3 and ADM are independently associated with the development of organ failure and adverse outcome in sepsis. We now discuss new evidence illustrating that these molecules indeed represent two distinct pathways involved in the development of septic shock. Recently, both ADM-enhancing therapies aimed at improving endothelial barrier function and vascular tone and DPP3-blocking therapies aimed at restoring systemic angiotensin responses have been shown to improve outcome in various preclinical sepsis models. Given the current lack of effective adjuvant therapies in sepsis, additional research on the therapeutic application of these peptides in humans is highly warranted. [ABSTRACT FROM AUTHOR]

Keywords: Osteogenesis imperfecta; bleeding disorders; vascular disease; platelet function tests; endothelial activation markers; hemorrhage EN Osteogenesis imperfecta bleeding disorders vascular disease platelet function tests endothelial activation markers hemorrhage 785 788 4 02/17/21 20210215 NES 210215 I Osteogenesis imperfecta i (OI) is a genetic disorder of connective tissue affecting bone formation and strength, resulting in susceptibility to spontaneous fracture. Based on Elbatarny's study, OI patients were classified according to their BS.3 BS < 3 correspond to patients with no evidence of bleeding history (OI NB for OI non-bleeders) and a BS >= 3 corresponds to patients with features of bleeding (OI B for OI bleeders). PHOTO (COLOR): 1 Determination of circulating VWF antigen level (A), VWF activity (B), secreted Thrombomodulin (C) and secreted E-selectin in OI group (D), OI NB and OI B subgroups. Platelet aggregation responses to several agonists expressed as maximal amplitude (% aggregation) (MA) after 4 min in the OI group, and in the OI NB and OI B subgroups. [Extracted from the article]

Anti‐vascular endothelial growth factor (VEGF) therapies are now the first‐line treatment for many ocular diseases, but some patients are non‐responders to these therapies. The purpose of this study was to determine whether the level of adiponectin increased the pathogenesis of retinal edema and neovascularization in the retina of progressive ocular vascular diseases. We examined the role played by adiponectin in two types of cells and animal models which are retinal vein occlusion (RVO) and oxygen‐induced retinopathy (OIR) mice. Our results showed that an injection of anti‐adiponectin antibody ameliorated the retinal edema and ischemia through the depression of the expression level of VEGF‐related factors and tight junction‐related proteins in the retina of RVO mice. The intravitreal injection of anti‐adiponectin antibody also decreased the degree of retinal neovascularization in an OIR mice. In addition, exposure of human retinal microvascular endothelial cells and human brain microvascular pericytes in culture to adiponectin increased both the vascular permeability and neovascularization through the increase of inflammatory factor and the dropout of the pericytes. These findings indicate that adiponectin plays a critical role in retinal edema and neovascularization, and adiponectin is a potential therapeutic target for the treatment of diabetic macular edema, proliferative diabetic retinopathy, and RVO. [ABSTRACT FROM AUTHOR]

Background: The benefits of best medical therapy (BMT) for secondary prevention of cardiovascular events in patients with peripheral arterial disease are well established. Guidelines recommend prescription of BMT should consist of anti‐platelet, statins and angiotensin‐converting enzyme inhibitor or angiotensin receptor blocking therapy, with evidence this regimen reduces cardiovascular mortality following vascular surgery and improves vascular bypass graft patency. This multicentre study examines the BMT prescription on discharge after infrainguinal bypass (IIB) in Australia and New Zealand (ANZ). Primary outcome measure was discharge prescription of three BMT pharmacological agents, defined for study purposes as an anti‐platelet/anti‐coagulant, a lipid‐lowering agent, and an anti‐hypertensive medication if hypertension was diagnosed. Methods: This study retrospectively examined discharge prescriptions and summaries of all patients discharged following IIB in five ANZ hospitals, between January 2015 and April 2018. Results: A total of 688 admissions for IIB were included (76.9% male; mean age 67.8 ± 12.0). A total of 72.4% of procedures were for chronic limb ischaemia, compared to acute limb ischaemia (12.6%), and aneurysmal disease (15%). The primary outcome of adherence with complete BMT prescription occurred in 66.9% of admissions. Anti‐thrombotic agents were most frequently prescribed (96.4%), followed by anti‐lipidaemic agents (82.1%). Of the patients with documented hypertension, 43.8% were not prescribed an angiotensin‐converting enzyme inhibitor/angiotensin receptor blocking, while 19.2% were discharged without any anti‐hypertensive medications. Conclusion: Almost one third of patients were not prescribed complete BMT following IIB. There is potential to improve the outcomes after IIB in ANZ through a focus on risk‐factor control and BMT prescription. [ABSTRACT FROM AUTHOR]

Pulse pressure naturally increases over time as individuals' age due to arteriosclerosis and diffuse vascular stiffening. However, the differential for widened pulse pressure is broad and includes causes of hyperdynamic circulation and high‐output heart failure, such as aortic regurgitation and hyperthyroidism. In the absence of an underlying cause, wide pulse pressure is a sign of deteriorating cardiovascular health and carries increased risk for mortality, disease progression, and adverse clinical outcomes in chronic diseases including cardiovascular disease and chronic kidney disease. Current emphasis of antihypertensive treatment on systolic and diastolic blood pressure does not always address pulse pressure, thus subjecting many patients to an independent risk factor for poor outcomes. Pulse pressure control is more successfully achieved with thiazide diuretics and long‐acting nitrates when compared to other antihypertensive agents, but further research is needed to quantify the additional benefits of pulse pressure control over conventional blood pressure therapy. This case review provides an overview of the pathogenesis, pathologic causes, and treatment of widened pulse pressure and evaluates current evidence for pulse pressure as a predictor of clinical outcomes. [ABSTRACT FROM AUTHOR]

We report a 74‐year‐old patient who developed an acute aortic syndrome (AAS) with intramural haematoma (IMH) during treatment with nintedanib, a tyrosine kinase inhibitor. As we suspected a role for nintedanib, this was immediately interrupted. Four months later, a computed tomographic angiography (CTA) showed significant regression of the IMH. Therefore, we state that, when patients use nintedanib and develop acute chest or back pain, diagnostic work‐up for AAS should be considered. Furthermore, other risk factors for AAS, such as hypertension, genetic diseases and comedication should be taken into account when prescription of medication of this class is considered. [ABSTRACT FROM AUTHOR]

Summary: Plant pathogens use effector proteins to promote host colonisation. The mode of action of effectors from root‐invading pathogens, such as Fusarium oxysporum (Fo), is poorly understood. Here, we investigated whether Fo effectors suppress pattern‐triggered immunity (PTI), and whether they enter host cells during infection.Eight candidate effectors of an Arabidopsis‐infecting Fo strain were expressed with and without signal peptide for secretion in Nicotiana benthamiana and their effect on flg22‐triggered and chitin‐triggered reactive oxidative species (ROS) burst was monitored. To detect uptake, effector biotinylation by an intracellular Arabidopsis‐produced biotin ligase was examined following root infection.Four effectors suppressed PTI signalling; two acted intracellularly and two apoplastically. Heterologous expression of a PTI‐suppressing effector in Arabidopsis enhanced bacterial susceptibility. Consistent with an intracellular activity, host cell uptake of five effectors, but not of the apoplastically acting ones, was detected in Fo‐infected Arabidopsis roots.Multiple Fo effectors targeted PTI signalling, uncovering a surprising overlap in infection strategies between foliar and root pathogens. Extracellular targeting of flg22 signalling by a microbial effector provides a new mechanism on how plant pathogens manipulate their host. Effector translocation appears independent of protein size, charge, presence of conserved motifs or the promoter driving its expression. [ABSTRACT FROM AUTHOR]

New Findings: What is the topic of this review?Altered perfusion distribution at skeletal muscle arteriolar bifurcations and how this is modified by development of chronic metabolic disease.What advances does it highlight?The outcome created is a distribution of erythrocytes in the distal microcirculation that is characterized by increased spatial heterogeneity and reduced flexibility such that mass transport/exchange within the network is impaired, with limited ability to respond to imposed challenges. This advances our understanding of how altered vascular structure and function with metabolic disease impairs perfusion to skeletal muscle at a level of resolution that would not be identified through bulk flow responses. This review is based on the presentation 'Shifted vascular optimization: the emergence of a new arteriolar behaviour with chronic metabolic disease', given at the Symposium 'Understanding Complex Behaviours in the Microcirculation: from Blood Flow to Oxygenation' during the Annual Meeting of the Physiological Society at the Aberdeen Exhibition and Conference Centre in Aberdeen, UK in July 2019. The past years of dedicated investigation on linkages between vascular (dys)function under conditions of elevated cardiovascular disease risk and tissue/organ performance have produced results and insights that frequently suffer from limited correlation and causation. Reaching out from this challenge, it was proposed that this may reflect a 'level of resolution' argument and that altered haemodynamic behaviour in vascular networks could be a stronger predictor of functional outcomes than higher resolution measures. Using this approach, we have determined that an attractor that describes the spatial and temporal shift in perfusion distribution at successive arteriolar bifurcations within the skeletal muscle is a strong predictor of functional outcomes within animals and provides novel insight into fundamental mechanistic contributors to altered patterns of intra‐muscular perfusion. This article focuses on the applicability and utility of the attractor in models of cardiovascular and metabolic disease risk of increasing severity. We will also discuss the utility of the attractor in terms of understanding the effectiveness of aggressive interventions for reversing established vasculopathy and perfusion impairments. [ABSTRACT FROM AUTHOR]

Among ageing‐related illnesses, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality causing one‐third of all deaths worldwide. Ageing evokes a number of functional, pharmacological and morphological changes in the vasculature, accompanied by a progressive failure of protective and homeostatic mechanisms, resulting in target organ damage. Impaired vasomotor, proliferation, migration, antithrombotic and anti‐inflammatory function in both the endothelial and vascular smooth muscle cells are parts of the vascular ageing phenotype. The endothelium regulates these functions by the release of a wide variety of active molecules including endothelium‐derived relaxing factors such as nitric oxide, prostacyclin (PGI2) and endothelium‐derived hyperpolarization (EDH). During ageing, a functional decay of the nitric oxide pathway takes place. Nitric oxide signals to VSMC and other important cell types for vascular homeostasis through the second messenger cyclic guanosine monophosphate (cGMP). Maintenance of proper cGMP levels is an important goal in sustainment of proper vascular function during ageing. For this purpose, different components can be targeted in this signalling system, and among them, phosphodiesterase‐1 (PDE1) and soluble guanylate cyclase (sGC) are crucial. This review focuses on the role of PDE1 and sGC in conditions that are relevant for vascular ageing. [ABSTRACT FROM AUTHOR]

We present a rare case of anomalous systemic arterial supply to normal basal segments of the left lower lobe. Plain computed tomography (CT) showed an occupancy lesion in the left lower lobe. Contrast CT and merged three‐dimensional (3D) image reconstruction showed that the anomalous systemic artery originated from the descending aorta and substituted the basilar segmental pulmonary artery and the arterial supply to the basilar segment of left lower lobe. We use the merged image reconstruction of 3D CT angiography and bronchography (3D‐CTAB) to depict the precise location and stereoscopic shape of this vascular malformation. Therefore, we think that these data add a novel comprehensive perspective on the diagnosis of the feature of malformation and treatment planning for this rare disease. [ABSTRACT FROM AUTHOR]

The International Working Group on the Diabetic Foot (IWGDF) has published evidence-based guidelines on the prevention and management of diabetic foot disease since 1999. This guideline is on the diagnosis, prognosis, and management of peripheral artery disease (PAD) in patients with foot ulcers and diabetes and updates the previous IWGDF Guideline. Up to 50% of patients with diabetes and foot ulceration have concurrent PAD, which confers a significantly elevated risk of adverse limb events and cardiovascular disease. We know that the diagnosis, prognosis, and treatment of these patients are markedly different to patients with diabetes who do not have PAD and yet there are few good quality studies addressing this important subset of patients. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to devise clinical questions and critically important outcomes in the patient-intervention-comparison-outcome (PICO) format, to conduct a systematic review of the medical-scientific literature, and to write recommendations and their rationale. The recommendations are based on the quality of evidence found in the systematic review, expert opinion where evidence was not available, and a weighing of the benefits and harms, patient preferences, feasibility and applicability, and costs related to the intervention. We here present the updated 2019 guidelines on diagnosis, prognosis, and management of PAD in patients with a foot ulcer and diabetes, and we suggest some key future topics of particular research interest. [ABSTRACT FROM AUTHOR]

Purpose: To study the relationship between pseudoexfoliation (PEX) and aortic aneurysm in a population with a high prevalence of PEX. Methods: Survival analyses were performed in a cohort of 735 residents aged 65–74 years, examined in a population survey in the municipality of Tierp, Sweden, 1984–1986. To expand the sample size, 1040 people were recruited by means of glaucoma case records established at the Eye Department in Tierp in 1978–2007. In this way, the cohort comprised 1775 subjects, representing more than 25 400 person‐years at risk. Medical records and autopsy reports were reviewed to identify subjects diagnosed with aneurysm. Those with a follow‐up time shorter than 1 year were excluded. Results: By the end of the study in September 2017, 60 new cases of aortic aneurysm had been found. Of these cases, 23% (14 subjects) were affected by PEX at baseline, compared with 28% among subjects without aneurysm. No association between PEX and aortic aneurysm was found (hazard ratio 0.97; 95% confidence interval 0.53–1.77). Conclusion: In this population‐based study, we were unable to verify a relationship between PEX and the development of aortic aneurysm. [ABSTRACT FROM AUTHOR]

Grange syndrome is an autosomal recessive condition characterized by arterial occlusions and hypertension. Syndactyly, brachydactyly, bone fragility, heart defects, and learning disabilities have also been reported. Loss‐of‐function variants in YY1AP1 have only recently been associated with Grange syndrome. YY1AP1 encodes for the transcription coactivator yin yang 1‐associated protein 1 which regulates smooth muscle cell proliferation and differentiation. We here report on three siblings with steno‐occlusive arterial disorder and syndactyly in two of them. Whole exome sequencing including near‐splice regions led to the identification of two intronic YY1AP1 variants which were predicted to interfere with normal splicing. Sanger sequencing demonstrated compound‐heterozygosity in all affected siblings. RT‐PCR analyses confirmed skipping of exon 6 on one allele and exonization of 22 bp in intron 6 on the other. This is the first report of biallelic YY1AP1 variants in noncoding regions and just the second family with multiple affected siblings. Therefore, our report further delineates the phenotypic spectrum of Grange syndrome. [ABSTRACT FROM AUTHOR]

Introduction: Treatment of non‐IgM type I cryoglobulinaemic vasculitis (CV) is challenging. Corticosteroids are first‐line therapy, but relapses are frequent leading to therapeutic escalation. Bortezomib is a proteasome inhibitor with rapid effect on monoclonal component. However, its use in non‐IgM type I CV has been barely reported. Objective: To assess the efficacy of bortezomib in non‐IgM type I CV. Method: Single‐centre case series of four patients with non‐IgM type I CV treated with bortezomib monotherapy. Results: Two men and two women, 60‐84 years old, received bortezomib monotherapy. Monoclonal component was IgG‐λ (n = 2), IgA‐λ and IgG‐κ. Clinical features were necrotic rash (n = 3), synovitis (n = 3) and sensitive neuropathy (n = 2). CV was refractory to corticosteroids (n = 4), cyclophosphamide (n = 3) and rituximab (n = 2). Three patients experienced dramatic clinical improvement with undetectable cryoglobulin after three cycles (bortezomib 1.3 mg/m2 weekly). Each patient relapsed 4‐18 months after treatment discontinuation. Bortezomib was unsuccessful after four cycles in one patient. Bortezomib toxicity included one pneumonia and 1 case of worsening neuropathic pain. Conclusion: Bortezomib in monotherapy should be considered as a valuable option in refractory non‐IgM type I CV because of its swift efficacy and acceptable tolerance profile. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNAs (miRNAs) are small non‐coding RNAs that regulate gene expression at a post‐transcriptional level via either the degradation or translational repression of a target mRNA. They play an irreplaceable role in angiogenesis by regulating the proliferation, differentiation, apoptosis, migration and tube formation of angiogenesis‐related cells, which are indispensable for multitudinous physiological and pathological processes, especially for the occurrence and development of vascular diseases. Imbalance between the regulation of miRNAs and angiogenesis may cause many diseases such as cancer, cardiovascular disease, aneurysm, Kawasaki disease, aortic dissection, phlebothrombosis and diabetic microvascular complication. Therefore, it is important to explore the essential role of miRNAs in angiogenesis, which might help to uncover new and effective therapeutic strategies for vascular diseases. This review focuses on the interactions between miRNAs and angiogenesis, and miRNA‐based biomarkers in the diagnosis, treatment and prognosis of angiogenesis‐related diseases, providing an update on the understanding of the clinical value of miRNAs in targeting angiogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Over‐production of reactive oxygen species (ROS) and resulting oxidative stress contribute to retinal damage in vascular diseases that include diabetic retinopathy, retinopathy of prematurity and major retinal vessel occlusions. NADPH oxidase (Nox) proteins are professional ROS‐generating enzymes, and therapeutic targeting in these diseases has strong appeal. Pharmacological inhibition of Nox4 reduces the severity of experimental retinal vasculopathy. We investigated the potential application of this drug approach in humans. Methods: Differential Nox enzyme expression was studied by real‐time‐quantitative polymerase chain reaction in primary human retinal endothelial cell isolates and a characterized human retinal endothelial cell line. Oxidative stress was triggered chemically in endothelial cells, by treatment with dimethyloxalylglycine (DMOG; 100 μM); Nox4 and vascular endothelial growth factor (VEGFA) transcript were measured; and production of ROS was detected by 2′,7′‐dichlorofluorescein. DMOG‐stimulated endothelial cells were treated with two Nox1/Nox4 inhibitors, GKT136901 and GKT137831; cell growth was monitored by DNA quantification, in addition to VEGFA transcript and ROS production. Results: Nox4 (isoform Nox4A) was the predominant Nox enzyme expressed by human retinal endothelial cells. Treatment with DMOG significantly increased endothelial cell expression of Nox4 over 72 h, accompanied by ROS production and increased VEGFA expression. Treatment with GKT136901 or GKT137831 significantly reduced DMOG‐induced ROS production and VEGFA expression by endothelial cells, and the inhibitory effect of DMOG on cell growth. Conclusions: Our findings in experiments on activated human retinal endothelial cells provide translational corroboration of studies in experimental models of retinal vasculopathy and support the therapeutic application of Nox4 inhibition by GKT136901 and GKT137831 in patients with retinal vascular diseases. [ABSTRACT FROM AUTHOR]

Abstract: Computerized retinal imaging technologies enable the static and dynamic measurement of a range of retinal microvascular parameters. Large population‐based studies have reported associations between these microvascular indices and various ophthalmic diseases including diabetes, age‐related macular degeneration, retinal artery embolism, retinal vein occlusion, glaucoma and non‐glaucomatous optic neuropathies. Increasingly, sophisticated imaging and analysis techniques have the potential to provide relevant clinical information regarding disease risk and progression; however, further studies are required to verify associations and strengthen the predictive power of these techniques. We summarize the current state of knowledge regarding retinal microvascular characteristics and eye disease. [ABSTRACT FROM AUTHOR]

Abstract: Allogeneic mesenchymal stromal cells (allo‐MSC) are a promising “off‐the‐shelf” therapy with anti‐inflammatory and pro‐repair properties. This study investigated humoral immune responses to intramuscular (IM) injections of allo‐MSC. Total and isotype‐specific anti‐donor IgG and donor‐specific complement‐mediated lysis were determined in sera from healthy mice 2 weeks after single or repeated IM injections of fully mismatched‐MHC allo‐MSC with comparison to mice receiving syngeneic MSC, allogeneic splenocytes or saline. In mice subjected to hind limb ischemia (HLI), anti‐donor IgG was analyzed following IM allo‐MSC injection with and without administration of the T‐cell immunosuppressant tacrolimus. Recipients of single and repeated IM allo‐MSC developed readily‐detectable anti‐donor IgG. Serum anti‐donor IgG levels were similar to those of allo‐splenocyte recipients but had higher IgG1/IgG2a ratio and variable capacity for complement‐mediated lysis of donor cells. The induced anti‐donor IgG bound readily to allo‐MSC and this binding was increased following allo‐MSC pretreatment with interferon gamma. In mice with HLI, IM injection of allo‐MSC into the ischemic limb was also associated with induction of anti‐donor IgG but this was abrogated by tacrolimus (FK‐506). The results indicate that allo‐MSC are inherently immunogenic when delivered intramuscularly to healthy and ischemic mouse hind limb, but induce an IgG1‐skewed humoral response that is suppressed by tacrolimus. [ABSTRACT FROM AUTHOR]

ABSTRACT: Mitochondria are highly dynamic organelles that constantly migrate, fuse, and divide to regulate their shape, size, number, and bioenergetic function. Mitofusins (Mfn1/2), optic atrophy 1 (OPA1), and dynamin‐related protein 1 (Drp1), are key regulators of mitochondrial fusion and fission. Mutations in these molecules are associated with severe neurodegenerative and non‐neurological diseases pointing to the importance of functional mitochondrial dynamics in normal cell physiology. In recent years, significant progress has been made in our understanding of mitochondrial dynamics, which has raised interest in defining the physiological roles of key regulators of fusion and fission and led to the identification of additional functions of Mfn2 in mitochondrial metabolism, cell signalling, and apoptosis. In this review, we summarize the current knowledge of the structural and functional properties of Mfn2 as well as its regulation in different tissues, and also discuss the consequences of aberrant Mfn2 expression. [ABSTRACT FROM AUTHOR]

Pediatric hypertension guidelines recommend Doppler renal ultrasonography as a screening study for the evaluation of possible renal artery stenosis (RAS) in normal-weight children ≥ 8 years of age who are suspected of having RAS and who will cooperate with the procedure. Obese children are excluded because of technical and vascular concerns. There are no data on RI in obese children. This is a retrospective review of children aged 1.5-18 who received Doppler imaging studies over a 10-year period. A total of 174 patients were studied. There was no significant difference between the RI values based on BMI. Of the 174 individuals in the study 22 obtained follow-up CT/MRA after abnormal Doppler ultrasounds. On advanced imaging 3 were confirmed to have RAS. Obesity does not seem to influence RI.RI alone should not be used as a screening tool for RAS. An approach toward diagnosis is suggested based on BMI, renin levels, and ultrasound. [ABSTRACT FROM AUTHOR]

Background and Purpose: Acetazolamide reactivity on 123 I-IMP SPECT is used to detect misery perfusion due to intracranial atherosclerosis. Noninvasive fractional flow assessed by signal intensity ratio (SIR) on time of flight-magnetic resonance angiography (TOF-MRA) might offer a feasible alternative to identify high-risk intracranial stenosis.Methods: Data from consecutive patients with unilateral middle cerebral artery (MCA) stenosis who underwent both TOF-MRA and acetazolamide reactivity on 123 I-IMP SPECT were retrospectively analyzed. Signal intensity was measured in the background and on the MCA proximal and distal to the stenotic lesion on TOF-MRA. Mean cerebral blood flow (CBF) at rest and cerebrovascular reactivity were measured in the target MCA territory. CBF patterns of the MCA were divided into three groups (Powers' stage 0-II).Results: A total of 56 sets of diagnostic imaging in 33 patients were assessed. Four CBF patterns were stage II in four MCA territories, stage I in 31, and stage 0 in 21. Median SIR of the MCA was .53 (interquartile range .46-.69) for stage II, .78 (.63-.90) for stage I, and .91 (.85-.95) for stage 0. The optimal cutoff for SIR obtained from receiver operating characteristic curve analysis to predict stage II was < .56.Conclusions: In patients with unilateral MCA stenosis, decreased SIR was correlated with misery perfusion, providing a simpler, widely available predictor of high-risk intracranial stenosis. [ABSTRACT FROM AUTHOR]

Abstract: The incidence of dementia is expected to double in the next 20 years and will contribute to heavy social and economic burden. Dementia is caused by neuronal loss that leads to brain atrophy years before symptoms manifest. Currently, no cure exists and extensive efforts are being made to mitigate cognitive impairment in late life in order to reduce the burden on patients, caregivers, and society. The most common type of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) often co‐exists in the brain and shares common, modifiable risk factors, which are targeted in numerous secondary prevention trials. There is a growing need for non‐pharmacological interventions and infrastructural support from governments to encourage psychosocial and behavioral interventions. Secondary prevention trials need to be redesigned based on the risk profile of individual subjects, which require the use of validated and standardized clinical, biological, and neuroimaging biomarkers. Multi‐domain approaches have been proposed in high‐risk populations that target optimal treatment; clinical trials need to recruit individuals at the highest risk of dementia before symptoms develop, thereby identifying an enriched disease group to test preventative and disease modifying strategies. The underlying aim should be to reduce microscopic brain tissue loss by modifying vascular and lifestyle risk factors over a relatively short period of time, thus optimizing the opportunity for preventing dementia in the future. Collaboration between international research groups is of key importance to the optimal use and allocation of existing resources, and the development of new techniques in preventing dementia. This article is part of the Special Issue “Vascular Dementia”. [ABSTRACT FROM AUTHOR]

Aims: Regional cerebral oxygen saturation (rSO2) is currently the most used measure in clinical practice to monitor cerebral ischaemia in patients undergoing carotid endarterectomy (CEA). Although end‐tidal carbon dioxide (PETCO2) is known as a factor that influences rSO2, the relationship between PETCO2 and rSO2 has not been quantitatively evaluated in patients with severe arteriosclerosis. This study aimed to evaluate the effect of PETCO2 on rSO2 in patients undergoing CEA under general anaesthesia. Methods: The intervention to change PETCO2 was conducted between skin incision and clamping of the carotid artery. The rSO2 values were observed by changing PETCO2 in the range of 25–45 mmHg. The PETCO2–rSO2 relationship was characterized by population analysis using a turnover model. Results: In total, 1651 rSO2 data points from 30 patients were used to determine the pharmacodynamic characteristics. Hypertension (HTN) and systolic blood pressure (SBP) were significant covariates on the slope factor in the stimulatory effect of PETCO2 on rSO2 and fractional turnover rate constant (kout), respectively. The estimates of the parameters were kout(min−1): 3.59 for SBP <90 mmHg and 0.491 for SBP ≥90 mmHg, slope: 0.00321 for patients with HTN and 0.00664 for patients without HTN. Conclusion: The presence of HTNattenuates the response of rSO2 after a change in PETCO2. When cerebral blood flow is in a state of decline caused by a decrease in SBP to <90 mmHg, the response of rSO2 to PETCO2 is increased. It is advisable to maintain SBP >90 mmHg in patients with HTNduring CEA. [ABSTRACT FROM AUTHOR]

S tudies have suggested an association between varicocele, hypogonadism, and elevated oxidative stress markers, but no other health risks have been associated with varicoceles. We sought to determine the association between varicocele and incident medical comorbidities. Using the Truven Health MarketScan® claims database from 2001 to 2009, we identified 4459 men with varicoceles, and 100,066 controls based on ICD-9 and CPT codes, with an average follow-up of 3.1 person years. Men with varicoceles were classified as symptomatic or asymptomatic based on co-existing diagnoses. Men with medical comorbidities present before or within 1 year of index diagnosis were excluded. Metabolic and cardiovascular outcome variables were identified via ICD-9 codes. A Cox regression analysis was used to assess incident risk of metabolic and cardiovascular disease amongst the different groups. Men with varicoceles had a higher incidence of heart disease compared to men who underwent infertility testing (HR 1.22, 95% CI: 1.03-1.45), and men who underwent vasectomy (HR 1.32, 95% CI 1.13-1.54). The varicoceles group also had a higher risk of diabetes (HR 1.73, 95% CI: 1.37-2.18) and hyperlipidemia (HR 1.15, 95% CI: 1.03-1.28) compared to the vasectomy group. Furthermore, men with symptomatic varicoceles ( n = 3442) had a higher risk of heart disease, diabetes, and hyperlipidemia following diagnosis, while men with asymptomatic varicoceles ( n = 1017) did not. Given the prevalence of varicoceles, further research is needed to understand the implications of a varicocele to a man's overall health. [ABSTRACT FROM AUTHOR]

Few studies have investigated the influence of age on the relationships between systemic vascular damage, kidney dysfunction, and intrarenal hemodynamic changes in patients with hypertension without overt cardiovascular disease. The authors enrolled 126 elderly patients with hypertension (aged ≥65 years) and 350 nonelderly patients with hypertension (aged <65 years). Carotid intima-media thickness, renal resistive index, and aortic pulse wave velocity were performed in all patients. Elderly patients with hypertension had lower estimated glomerular filtration rates and higher albuminuria, renal resistive index, carotid intima-media thickness, and aortic pulse wave velocity compared with nonelderly patients with hypertension (P < .001). Carotid intima-media thickness independently correlated with renal resistive index and estimated glomerular filtration rate in nonelderly patients with hypertension, whereas it was significantly related to renal resistive index only in elderly patients with hypertension. Aortic pulse wave velocity was independently associated with albuminuria in nonelderly patients with hypertension, whereas it did not independently correlate with any indexes of renal damage in elderly patients with hypertension. Age is an important modifier of the relationships between renal function and renal hemodynamics with subclinical vascular involvement in elderly persons without cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Spontaneous cervical artery dissection (sCAD) is an important etiology of juvenile stroke. The gold standard for the diagnosis of sCAD is convential angiography. However, magnetic resonance imaging (MRI)/MR angiography (MRA) and computed tomography (CT)/CT angiography (CTA) are frequently used alternatives. New developments such as multislice CT/CTA have enabled routine acquisition of thinner sections with rapid imaging times. The goal of this study was to compare the capability of recent developed 128-slice CT/CTA to MRI/MRA to detect radiologic features of sCAD.Methods: Retrospective review of patients with suspected sCAD (n = 188) in a database of our Stroke center (2008-2014), who underwent CT/CTA and MRI/MRA on initial clinical work-up. A control group of 26 patients was added. All Images were evaluated concerning specific and sensitive radiological features for dissection by two experienced neuroradiologists. Imaging features were compared between the two modalities.Results: Forty patients with 43 dissected arteries received both modalities (29 internal carotid arteries [ICAs] and 14 vertebral arteries [VAs]). All CADs were identified in CT/CTA and MRI/MRA. The features intimal flap, stenosis, and lumen irregularity appeared in both modalities. One high-grade stenosis was identified by CT/CTA that was expected occluded on MRI/MRA. Two MRI/MRA-confirmed pseudoaneurysms were missed by CT/CTA. None of the controls evidenced specific imaging signs for dissection.Conclusions: CT/CTA is a reliable and better available alternative to MRI/MRA for diagnosis of sCAD. CT/CTA should be used to complement MRI/MRA in cases where MRI/MRA suggests occlusion. [ABSTRACT FROM AUTHOR]

Background: Ischaemic stroke and coronary heart disease are important contributors to the global disease burden and share atherosclerosis as the main underlying cause. Recent evidence from a genome-wide association study (GWAS) suggested that single nucleotide polymorphisms (SNP) near the MMP12 gene at chromosome 11q22.3 were associated with large-vessel ischaemic stroke. Here, we evaluated and extended these results by examining the relationship between MMP12 and atherosclerosis in clinical and experimental studies.Methods and Results: Plasma concentrations of MMP12 were measured at baseline in 3394 subjects with high-risk for cardiovascular disease (CVD) using the Olink ProSeek CVD I array. The plasma MMP12 concentration showed association with incident cardiovascular and cerebrovascular events (130 and 67 events, respectively, over 36 months) and carotid intima-media thickness progression (P = 3.6 × 10-5 ). A GWAS of plasma MMP12 concentrations revealed that SNPs rs499459, rs613084 and rs1892971 at chr11q22.3 were independently associated with plasma MMP12 (P < 5 × 10-8 ). The lead SNPs showed associations with mRNA levels of MMP12 and adjacent MMPs in atherosclerotic plaques. MMP12 transcriptomic and proteomic levels were strongly significantly increased in carotid plaques compared with control arterial tissue and in plaques from symptomatic versus asymptomatic patients. By combining immunohistochemistry and proximity ligation assay, we demonstrated that MMP12 localizes to CD68 + macrophages and interacts with elastin in plaques. MMP12 silencing in human THP-1-derived macrophages resulted in reduced macrophage migration.Conclusions: Our study supports the notion that MMP12 is implicated in large-artery atherosclerotic stroke, functionally by enhancing elastin degradation and macrophage invasion in plaques. [ABSTRACT FROM AUTHOR]

This retrospective cohort study compared blood pressure (BP) control (BP <140/90 mm Hg) and all-cause mortality between US- and foreign-born blacks. We used data from a clinical data warehouse of 41 868 patients with hypertension who received care in a New York City public healthcare system between 2004 and 2009, defining BP control as the last recorded BP measurement and mean BP control. Poisson regression demonstrated that Caribbean-born blacks had lower BP control for the last BP measurement compared with US- and West African-born blacks, respectively (49% vs 54% and 57%; P<.001). This pattern was similar for mean BP control. Caribbean- and West African-born blacks showed reduced hazard ratios of mortality (0.46 [95% CI, 0.42-0.50] and 0.28 [95% CI, 0.18-0.41], respectively) compared with US-born blacks, even after adjustment for BP. BP control rates and mortality were heterogeneous in this sample. Caribbean-born blacks showed worse control than US-born blacks. However, US-born blacks experienced increased hazard of mortality. This suggests the need to account for the variations within blacks in hypertension management. [ABSTRACT FROM AUTHOR]

Aim The aim of the present study was to investigate whether increasing the bosentan dosing frequency from 2 mg kg-1 twice daily (b.i.d.) to 2 mg kg-1 three times daily (t.i.d.) in children with pulmonary arterial hypertension (PAH) (from ≥3 months to <12 years of age) would increase exposure. Methods An open-label, prospective, randomized, multicentre, multiple-dose, phase III study was conducted. Patients ( n = 64) were randomized 1:1 to receive oral doses of bosentan of 2 mg kg-1 b.i.d. or t.i.d. The main pharmacokinetic endpoint was the daily exposure to bosentan over 24 h corrected to the 2 mg kg-1 dose (AUC0-24C). The maximum plasma concentration corrected to the 2 mg kg-1 dose (CmaxC), the time to reach the maximum plasma concentration (tmax) and safety endpoints were also assessed. Results The geometric mean [95% confidence interval (CI)] for AUC0-24C was 8535 h.ng ml-1 (6936, 10 504) and 7275 h.ng ml-1 (5468, 9679) for 2 mg kg-1 b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.85 (0.61, 1.20)]. The geometric mean (95% CI) for CmaxC was 743 ng ml-1 (573, 963) and 528 ng ml-1 (386, 722) for 2 mg kg-1 b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.71 (0.48, 1.05)]. The median (range) for tmax was 3.0 h (0.0-7.5) and 3.0 h (1.0-8.0) for 2 mg kg-1 b.i.d. and t.i.d., respectively. The proportions of patients who experienced ≥1 adverse event were similar in the b.i.d. (66.7%) and t.i.d. (67.7%) groups. Conclusions There appeared to be no clinically relevant difference in exposure to bosentan, or in safety, when increasing the frequency of bosentan dosing from b.i.d. to t.i.d. Therefore, the present study provides no indication that the dosing recommendation should be changed, and 2 mg kg-1 b.i.d. remains the recommended dosing regimen for bosentan in paediatric PAH patients. [ABSTRACT FROM AUTHOR]

Lentil ( Lens culinaris Medik.) is an important food legume crop in Syria. Fusarium wilt ( Fusarium oxysporum f.sp. lentis - Fol) is a key yield-limiting factor in the country. The genetic diversity of Fol population was studied using 96 isolates collected from different parts of the country using molecular markers. A total of 16 markers, random amplified polymorphic DNA, simple sequence repeats and inter-simple sequence repeats were used and 218 polymorphic markers (scorable bands) were obtained. Cluster and structure analyses grouped the isolates into three major groups and subgroups indicating high genetic diversity in the pathogen populations. The molecular variance within the population accounted 87% of the total variation indicating high diversity within population than among geographic locations. The result of this study showed that no alleles were linked to specific province, and therefore, screening for the Fusarium wilt in one location using virulent isolates could be enough to save time and resources. [ABSTRACT FROM AUTHOR]