Evaluation of the degree of vascular breast calcifications on digital mammograms: A comparative analysis of the informative values of visual qualitative assessment and automated quantification

Vascular calcification (VC) is a common complication of chronic kidney disease (CKD). VC is a gene-regulated process similar to osteogenic differentiation. There are still no convincing schemes to prevent and reduce the development of VC. It has been reported that hypoxia-inducing factor 1α (HIF-1α) and endothelin-1(ET-1) are related to VC. In this study, we found that the expression of ET-1 and HIF-1α was enhanced after VC, the interaction between HIF-1α and ET-1 was confirmed by CO-IP and luciferase experiments. We found that ET-1 was an upregulated differential gene of calcified vascular smooth muscle cells (VSMCs) through gene sequencing. However, hypoxia-inducing factor 2α (HIF-2α) and HIF-1α have antagonistic effects on each other. HIF-1α is a pro-inflammatory cytokine, and HIF-2α can improve inflammation and fibrosis. Roxadustat, as a selective PHD3 inhibitor, preferentially activates HIF-2α. It is still unclear whether roxadustat improves VC in CKD by regulating the expression of HIF-2α/HIF-1α. Alizarin red staining and western blot as well as immunohistochemical results showed that roxadustat could significantly reduce the degree of vascular and VSMCs calcification in CKD rats. Serum HIF-1α and ET-1 were significantly decreased after roxadustat treatment. In addition, western blot results showed that roxadustat could decrease the expression of HIF-1α and ET-1 in vascular tissues and calcified VSMC, but HIF-2α expression significantly increased. Interestingly, our study confirmed that activation of HIF-1α or inhibition of HIF-2α reversed the ameliorating effect of roxadustat on VC, proving that the effect mediated by roxadustat is HIF-2α/HIF-1α dependent. We have demonstrated for the first time that roxadustat improves VC in CKD rats by regulating HIF-2α/HIF-1α, thus providing a new idea for the application of roxadustat in VC of CKD.

Chemical and hormonal determinants of vascular calcification in vitro

Effect of Training on Qualitative Mammographic Density Assessment

Mesial temporal sclerosis (MTS) is the most common pathology in patients undergoing anterior temporal lobectomy. Magnetic resonance imaging (MRI) is valuable in detecting MTS. Reduced hippocampal volume and elevated T2 signal are associated with MTS, and both quantitative T2 and volumetric measurementshave been associated with hippocampal cellular loss that characterizes this condition. Objectives: To determine the accuracy of hippocampal quantitative (T2 relaxometric) assessment in diagnosing hippocampal atrophy in patients with temporal lobe epilepsy by comparing it with qualitative (visual) assessment on MRI. Study Design: Cross sectional study. Setting: Radiology department of Allied Hospital Faisalabad. Period: 12 months from theapproval from Sep, 2016 to Dec, 2017. Subjects & Methods: After taking permission from hospital ethical committee, and written informed consent, patients with history of temporal lobe epilepsy and EEG findings consistent with temporal lobe epilepsy were examined on 1.5 Tesla Achieva philips scanner, visual assessment and T2 relaxometry. Section of the hippocampus head was defined as the first in which it was possible to see the temporal horn of the lateral ventricle and therefore to appropriately separate the hippocampal formation from the amygdala. The body of the hippocampus defined in the fourth coronal section after the region of interest of the hippocampus head, and the tail was defined in the third coronal section after the hippocampus body, in which it is also possible to visualize the quadrigeminal plate (section of 5mm).Visually the images were assessed and MRI examination was done. All the data was collected on a performa. Results: We concluded that the frequency of accuracy of hippocampal quantitative (t2 relaxometric) assessment in diagnosing hippocampal atrophy in patients with temporal lobe epilepsy by comparing it with qualitative (visual) assessment on MRIis high but needs validation through some-other studies. Conclusion: We concluded that the frequency of accuracy of hippocampal quantitative (t2 relaxometric) assessment in diagnosing hippocampal atrophy in patients with temporal lobe epilepsy by comparing it with qualitative (visual) assessment on MRI is high but needs validation through some-other studies.

In the current issue of Circulation , Ix et al demonstrate an inverse correlation between mitral and aortic valve calcification and serum fetuin-A levels in a cross-sectional study of 970 patients with coronary artery disease and without renal disease.1 Increased serum fetuin was significantly associated with diabetes mellitus, hypertriglyceridemia, serum albumin, and body mass index, with a weaker association with serum C-reactive protein, low-density lipoprotein cholesterol, and serum calcium. The link between aortic stenosis and fetuin held only in those without diabetes.1 The data highlight the complex interactions of fetuin with inflammation, insulin resistance, and tissue calcification. Furthermore, the results, though intriguing, underscore our lack of understanding of the cellular mechanisms of calcification in diverse pathological substrates, such as the degenerating aortic leaflet and mitral annulus. Article p 2533 Fetuin is a member of the cystatin superfamily of cysteine protease inhibitors, originally discovered as the major component of fetal bovine serum. It is a carrier for growth factors, binds to and inactivates transforming growth factor (TGF)–β and bone morphogenic protein, and is a major component of mineralized bone.2 Fetuin-A is also an acute-phase glycoprotein, produced in adults primarily in the liver, and is a powerful circulating inhibitor of hydroxyapatite formation. Mice that lack fetuin-A exhibit extensive soft-tissue calcification, which is accelerated on a mineral-rich diet, which suggests that fetuin-A acts to inhibit calcification systemically.3 In addition to its effects on mineralization, fetuin-A inhibits insulin receptor autophosphorylation and tyrosine kinase activity in vitro and in vivo. Fetuin-null knockout mice demonstrate improved insulin sensitivity and resistance to diet-induced obesity, and it has been postulated that the absence of fetuin in mice may contribute to the improvement of insulin sensitivity associated with aging.4 Clinically, serum fetuin-A is decreased in patients with moderate to severe chronic kidney disease, especially …

Vascular calcification has a global health impact that is closely linked to bone loss. The Receptor Activator of Nuclear Factor Kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, fundamental for bone metabolism, also plays an important role in vascular calcification. The Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a novel receptor for RANKL, regulates bone remodeling, and it appears to be involved in vascular calcification. Besides RANKL, LGR4 interacts with R-spondins (RSPOs), which are known for their roles in bone but are less understood in vascular calcification. Studies were conducted in rats with chronic renal failure fed normal or high phosphorus diets for 18 weeks, with and without control of circulating parathormone (PTH) levels, resulting in different degrees of aortic calcification. Additionally, vascular smooth muscle cells (VSMCs) were cultured under non-calcifying (1 mM phosphate) and calcifying (3 mM phosphate) media with different concentrations of PTH. To explore the role of RANKL in VSMC calcification, increasing concentrations of soluble RANKL were added to non-calcifying and calcifying media. The effects mediated by RANKL binding to its receptor LGR4 were investigated by silencing the LGR4 receptor in VSMCs. Furthermore, the gene expression of the RANK/RANKL/OPG system and the ligands of LGR4 was assessed in human epigastric arteries obtained from kidney transplant recipients with calcification scores (Kauppila Index). Increased aortic calcium in rats coincided with elevated systolic blood pressure, upregulated Lgr4 and Rankl gene expression, downregulated Opg gene expression, and higher serum RANKL/OPG ratio without changes in Rspos gene expression. Elevated phosphate in vitro increased calcium content and expression of Rankl and Lgr4 while reducing Opg. Elevated PTH in the presence of high phosphate exacerbated the increase in calcium content. No changes in Rspos were observed under the conditions employed. The addition of soluble RANKL to VSMCs induced genotypic differentiation and calcification, partly prevented by LGR4 silencing. In the epigastric arteries of individuals presenting vascular calcification, the gene expression of RANKL was higher. While RSPOs show minimal impact on VSMC calcification, RANKL, interacting with LGR4, drives osteogenic differentiation in VSMCs, unveiling a novel mechanism beyond RANKL-RANK binding.

Vascular access calcification predicts mortality in hemodialysis patients

Dyslipidemia and progression of cardiovascular calcification (CVC) in patients with end-stage renal disease (ESRD)

Background: Autophagy is a highly conserved catabolic homeostatic process, crucial for cell survival. It has been shown that autophagy can modulate different cardiovascular pathologies, including vascular calcification (VCN). Objective: To assess how modulation of autophagy, either through induction or inhibition, affects vascular and valvular calcification and to determine the therapeutic applicability of inducing autophagy. Data sources: A systematic review of English language articles using MEDLINE/PubMed, Web of Science (WoS) and the Cochrane library. The search terms included autophagy, autolysosome, mitophagy, endoplasmic reticulum (ER)-phagy, lysosomal, calcification and calcinosis. Study characteristics: Thirty-seven articles were selected based on pre-defined eligibility criteria. Thirty-three studies (89%) studied vascular smooth muscle cell (VSMC) calcification of which 27 (82%) studies investigated autophagy and six (18%) studies lysosomal function in VCN. Four studies (11%) studied aortic valve calcification (AVCN). Thirty-four studies were published in the time period 2015–2020 (92%). Conclusion: There is compelling evidence that both autophagy and lysosomal function are critical regulators of VCN, which opens new perspectives for treatment strategies. However, there are still challenges to overcome, such as the development of more selective pharmacological agents and standardization of methods to measure autophagic flux.

Intimal vascular calcification is an important marker of atherosclerosis, and its severity is an independent risk factor for cardiovascular events. Measurement of coronary or aortic calcification requires CT-based imaging and elaborate data analysis to ensure accuracy. A blood assay which could quantify the severity of vascular calcification would be less expensive, avoid exposure to radiation, and be more accessible than present imaging based methods. Osteoprotegerin (OPG) and osteopontin (OPN) are present in human serum and have been implicated in vascular calcification. In this prospective study we assessed the value of a number of serum assays for OPG and OPN in determining abdominal aortic calcification. Firstly, we investigated the assay characteristics and reproducibility of 5 ELISAs using a subset of patients. Based on the findings of these assessments, we selected 3 assays for full evaluation in the entire cohort.

Response evaluation at regular intervals is indicated for treatment of metastatic breast cancer (MBC). FDG-PET/CT has the potential to monitor treatment response accurately. Our purpose was to: (a) compare the interrater agreement and reliability of the semi-quantitative PERCIST criteria to qualitative visual assessment in response evaluation of MBC and (b) investigate the intrarater agreement when comparing visual assessment of each rater to their respective PERCIST assessment. We performed a retrospective study on FDG-PET/CT in women who received treatment for MBC. Three specialists in nuclear medicine categorized response evaluation by qualitative assessment and standardized one-lesion PERCIST assessment. The scans were categorized into complete metabolic response, partial metabolic response, stable metabolic disease, and progressive metabolic disease. 37 patients with 179 scans were included. Visual assessment categorization yielded moderate agreement with an overall proportion of agreement (PoA) between raters of 0.52 (95% CI 0.44–0.66) and a Fleiss kappa estimate of 0.54 (95% CI 0.46–0.62). PERCIST response categorization yielded substantial agreement with an overall PoA of 0.65 (95% CI 0.57–0.73) and a Fleiss kappa estimate of 0.68 (95% CI 0.60–0.75). The difference in PoA between overall estimates for PERCIST and visual assessment was 0.13 (95% CI 0.06–0.21; p = 0.001), that of kappa was 0.14 (95% CI 0.06–0.21; p < 0.001). The overall intrarater PoA was 0.80 (95% CI 0.75–0.84) with substantial agreement by a Fleiss kappa of 0.74 (95% CI 0.69–0.79). Semi-quantitative PERCIST assessment achieved significantly higher level of overall agreement and reliability compared with qualitative assessment among three raters. The achieved high levels of intrarater agreement indicated no obvious conflicting elements between the two methods. PERCIST assessment may, therefore, give more consistent interpretations between raters when using FDG-PET/CT for response evaluation in MBC.

Abstract. Introduction. Currently, mammography is widely used in the routine clinical practice and, along with detecting the changes that may be indicative of breast carcinoma, allows assessing the unaltered breast parenchyma and its feeding vessels with the diameter of at least 0.5 mm, particularly regarding calcifications. Hypothyroidism represents the deficiency of thyroid hormones, which is relatively frequently seen in the clinical routine and associated with multiple unfavorable outcomes. Aim: To present a series of clinical cases where we found typical breast vascular calcifications in female patients at mammography. Materials and Methods. This paper describes 3 patients of this type with long- standing uncompensated hypothyroidism, all having pronounced vascular breast calcifications. Results and Discussion. All the patients had no significant cardiovascular pathologies both at the first detection of vascular calcifications and during their 5-year follow-up. Hypothyroidism is associated with the decreased overall survival as compared to the euthyroid patients, particularly because it also increases the risk of chronic kidney insufficiency, adhesive shoulder capsulitis, senile macular degeneration, myocardial infarction, and chronic cardiac insufficiency. This makes timely identifying such patients very important. Conclusion. Pronounced vascular calcifications at mammography may be the marker of the chronic thyroid insufficiency. Moreover, this phenomenon and the link between such changes and adverse cardiovascular outcomes needs to be clarified in future clarification.

Vascular calcification (VC) is known to be prevalent in patients with end-stage renal disease (ESRD). Sclerostin has been identified to be involved in the cross-talk between the kidney, vasculature, and bone. The aims of the present study were to evaluate vessel sclerostin expression and its correlation with VC, as well as serum sclerostin levels. A total of 51 adult ESRD patients undergoing living donor renal transplant (RT) were enrolled in this study. Serum sclerostin levels were measured by enzyme-linked immunosorbent assays. The thoracic aorta calcification (TAC) was measured by computed tomography (CT). The aortic calcification area index (ACAI) was used to evaluate the severity of TAC. During the RT surgery, the internal iliac arteries were collected and paraffin-embedded in 40 patients, followed by immunohistochemical staining for sclerostin expression and von Kossa-staining for vascular medial calcification degree. The prevalence rate of TAC detected by CT was 58.82%. The positive rates of the internal iliac arterial calcification and vessel sclerostin expression were both 45%. Vessel sclerostin was strongly co-localized with medial calcification. Multivariate analyses revealed that only serum sclerostin was significantly associated with the presence of TAC, the severity of TAC and the positive expression of vessel sclerostin. Kappa test showed that the consistency of the two different calcification assessment methods, as well as the consistency of vessel sclerostin expression and von Kossa-staining were high. Furthermore, the cutoff points of serum sclerostin for vessel sclerostin expression, the presence of VC evaluated by CT and that evaluated by pathology were 1599.92pg/mL, 2475.52pg/mL, and 2116.23pg/mL, respectively. The two methods, namely CT and pathology, to evaluate VC were highly consistent. Serum sclerostin was an independent determinant of positive expression of vessel sclerostin and VC in ESRD patients eligible for RT.

Objective To analyze the changes of serum sclerostin in uremic patients and its correlation with vascular calcification. Methods Forty-five uremic patients who had been admitted to the hospital between March 2016 and March 2018 were selected as the observation group, and 45 healthy subjects after taking cardiac ultrasound and abdominal plain radiograph examination in the hospital during the same period were selected as the control group. All patients enrolled received general data investigations and examinations of clinical indicators including calcium (Ca), phosphorus (P), magnesium (Mg), albumin (ALB), total cholesterol (CHOL), triglyceride (TG), low density lipoprotein (LDL), intact parathyroid hormone (IPTH), and serum sclerostin, and abdominal X-ray examination was performed on all patients to determine the degree of vascular calcification. Results The main primary disease in uremic patients in the hospital was metabolic disease. There was no significant difference between the two groups in gender and body mass index (P<0.05). The levels of ALB, TG, LDL, HDL, Ca and Mg in the uremic patients were all lower than those in the control group.The CHOL, incidence of calcification, iPTH, P, serum sclerostin, and vascular calcification in the uremic patients were all higher than those in the control group, where the difference was statistically significant(P<0.05). Older age, diabetes mellitus and hypertension, and longer dialysis time were the main causes of high levels of serum sclerostin in uremic patients. The lower the level of serum sclerostin, the higher the levels of CHOL, LDL, iPTH and P. The lower the levels of ALB, Ca and Mg, the higher the degree of vascular calcification; the difference was statistically significant(P<0.05). The level of serum sclerostin in uremic patients was negatively correlated with age, iPTH, P, degree of vascular calcification, and positively correlated with the level of ALB and Mg(P<0.05). Conclusions Vascular calcification is prevalent and severe in patients with uremia. The high level of serum sclerostin in uremic patients might be associated with the degree of vascular calcification. Serum sclerostin may serve as a new and important indicator of vascular calcification and bone turnover in uremic patients. Key words: Uremia; Glycoproteins; Vascular Calcification

Background and Aims Bone-mineral disease and vascular calcification are common complications in hemodialysis. The harmony between parathyroid hormone, calcium and phosphorus is impaired during hemodialysis and it supposed to be reversed by kidney transplantation but it is not known if the effect on vascular calcification will be reversed. Our aim is to study renal transplantation effect on hemodialysis associated vascular calcification and the risk factors for development and progression of vascular calcification. Method Transplant registry in Mansoura Urology and Nephrology Center, Egypt was reviewed for kidney transplant recipients (KTRs) who received renal allo-transplantation between January 2016 and December 2017 (149 KTRs). Patients were divided according to the presence of vascular calcification using non-contrast CT into 2 groups. Group I: 58 KTRs with pre-transplant vascular calcification, Group II: 91 KTRs without pre-transplant vascular calcification. Group I then were subdivided into 3 groups according to Agatston score (coronary calcium score) to 3 groups: Mild calcification (11-100), Moderate calcification (101-400), Severe calcification (&amp;gt;400). All patients were screened for coronary vascular calcification 2 years after transplantation using multi-slice coronary CT. Patients with detectable CAC at baseline and a CAC score change was ≥25% and patient with CAC score of 0 and follow up ≥ 4 were considered as progressors. Results The recipients` age in both group ranged from 18 years to 55 years. Older age is associated with higher incidence of vascular calcification (p value: 0.048) with male predominance and mean body mass index is 32.5±2.3. Majority of patients underwent hemodialysis before transplantation (90%). The longer hemodialysis duration, the more severe the degree of vascular calcification (p value: 0.003). There was no difference among both groups regarding CKD bone-mineral biomarkers except for intact PTH which was higher among vascular calcification patients (p value: 0.023). The majority of our patients received induction therapy; Basiliximab and received tacrolimus based immunosuppressive regimen. There was no significant difference regarding rejection episodes or post-transplant medical disorders. Presence of vascular calcification did not affect graft outcome over 2 years. Despite significant improvement in CKD-bone disease biomarkers (p value: 0.001; calcium, phosphorus, alk. phosphatase and intact PTH changes), Vascular calcification incidence increased after transplantation from 38.9% to 40.9% especially for severe form with rise of median agatston score from 258.85 (21,813) to 354.55(20, 1198.8). Patients were divided according to progression into 2 groups: progressors (59 KTRs) and non-progressors (90 KTRs). On comparison of both groups, there were 3 independent risk factors for CAC progression: pre-transplant Calcium score (Figure 1), dialysis duration (Figure 2) and pre-transplant PTH level (Figure 3) with significant p value: &amp;lt;0.001, &amp;lt;0.001 and 0.05 respectively. Pre-emptive transplantation is inversely proportional in determining CAC progression with p value: 0.02. ROC curve analyses were performed to evaluate the discriminatory power of the three parameters. Conclusion Baseline CAC, duration of dialysis and pre-transplant serum PTH level are factors associated CAC progression. Renal transplantation does not stop or reverse CAC. Progression of CAC is the usual evolution pattern of CAC in renal transplant recipients. Very important was the finding that the follow-up calcium Score was significantly related to the baseline score., which emphasizes the importance of primary prevention of CAC development.