Robustness of DNA looping across multiple cell divisions in individual bacteria.

DNA looping has emerged as a central paradigm of transcriptional regulation, as it is shared across many living systems. One core property of DNA looping-based regulation is its ability to greatly enhance repression or activation of genes with only a few copies of transcriptional regulators. However, this property based on a small number of proteins raises the question of the robustness of such a mechanism with respect to the large intracellular perturbations taking place during growth and division of the cell. Here we address the issue of sensitivity to variations of intracellular parameters of gene regulation by DNA looping. We use the lac system as a prototype to experimentally identify the key features of the robustness of DNA looping in growing Escherichia coli cells. Surprisingly, we observe time intervals of tight repression spanning across division events, which can sometimes exceed 10 generations. Remarkably, the distribution of such long time intervals exhibits memoryless statistics that is mostly insensitive to repressor concentration, cell division events, and the number of distinct loops accessible to the system. By contrast, gene regulation becomes highly sensitive to these perturbations when DNA looping is absent. Using stochastic simulations, we propose that the observed robustness to division emerges from the competition between fast, multiple rebinding events of repressors and slow initiation rate of the RNA polymerase. We argue that fast rebinding events are a direct consequence of DNA looping that ensures robust gene repression across a range of intracellular perturbations.

Resonant learning in scale-free networks.

Large networks of interconnected components, such as genes or machines, can coordinate complex behavioral dynamics. One outstanding question has been to identify the design principles that allow such networks to learn new behaviors. Here, we use Boolean networks as prototypes to demonstrate how periodic activation of network hubs provides a network-level advantage in evolutionary learning. Surprisingly, we find that a network can simultaneously learn distinct target functions upon distinct hub oscillations. We term this emergent property resonant learning, as the new selected dynamical behaviors depend on the choice of the period of the hub oscillations. Furthermore, this procedure accelerates the learning of new behaviors by an order of magnitude faster than without oscillations. While it is well-established that modular network architecture can be selected through evolutionary learning to produce different network behaviors, forced hub oscillations emerge as an alternative evolutionary learning strategy for which network modularity is not necessarily required.

Prevalence, patterns and outcomes of cardiac involvement in Erdheim-Chester disease.

AIMS: Cardiac involvement of Erdheim-Chester disease (ECD), a rare L group histiocytosis, has been reported to be associated with poor outcomes, but systematic studies are lacking. The present study aimed to investigate the prevalence, clinical features, imaging features, and prognosis of cardiac involvement in ECD in a large series. METHODS AND RESULTS: All patients with ECD who underwent cardiac magnetic resonance (CMR) imaging between 2003 and 2019 at a French tertiary center were retrospectively included. Primary outcome was all-cause mortality. Secondary outcomes were pericarditis, cardiac tamponade, conduction disorders, device implantation and coronary artery disease (CAD). A total of 200 patients were included [63 (54-71) years, 30% female, 58% BRAFV600E mutated]. Median follow-up was 5.5 years (3.3-9 years). On CMR, right atrioventricular sulcus infiltration was observed in 37% of patients, and pericardial effusion was seen in 24% of patients. In total, 8 patients (4%) had pericarditis (7 acute, 1 constrictive), 10 patients (5%) had cardiac tamponade, 5 patients (2.5%) had ECD-related high-degree conduction disorders, and 45 patients (23%) had CAD. Overall, cardiac involvement was present in 96 patients (48%) and was associated with BRAFV600E mutation [Odds ratio (OR) = 7.4, 95% confidence interval (CI) (3.5-16.8), P < 0.001] and ECD-related clinical events [OR = 5, 95%CI (1.5-21.2), P = 0.004] but not with lower survival in multivariate analysis [adjusted hazard ratio (HR) = 1.4, 95% CI (0.8-2.5), P = 0.2]. CONCLUSION: Cardiac involvement is present in nearly half of ECD patients and is associated with BRAFV600E mutation and complications (pericarditis, cardiac tamponade, and conduction disorders) but not with lower survival.

Filtering input fluctuations in intensity and in time underlies stochastic transcriptional pulses without feedback.

Stochastic pulsatile dynamics have been observed in an increasing number of biological circuits with known mechanism involving feedback control and bistability. Surprisingly, recent single-cell experiments in Escherichia coli flagellar synthesis showed that flagellar genes are activated in stochastic pulses without the means of feedback. However, the mechanism for pulse generation in these feedbackless circuits has remained unclear. Here, by developing a system-level stochastic model constrained by a large set of single-cell E. coli flagellar synthesis data from different strains and mutants, we identify the general underlying design principles for generating stochastic transcriptional pulses without feedback. Our study shows that an inhibitor (YdiV) of the transcription factor (FlhDC) creates a monotonic ultrasensitive switch that serves as a digital filter to eliminate small-amplitude FlhDC fluctuations. Furthermore, we find that the high-frequency (fast) fluctuations of FlhDC are filtered out by integration over a timescale longer than the timescale of the input fluctuations. Together, our results reveal a filter-and-integrate design for generating stochastic pulses without feedback. This filter-and-integrate mechanism enables a general strategy for cells to avoid premature activation of the expensive downstream gene expression by filtering input fluctuations in both intensity and time so that the system only responds to input signals that are both strong and persistent.

Cerebrovascular Ischemic Events in Patients With Takayasu Arteritis.

BACKGROUND: Takayasu arteritis (TA) is a large vessel vasculitis that may complicate with cerebrovascular ischemic events. The objective was to describe clinical and vascular features of TA patients with cerebrovascular ischemic events and to identify risk factors for these events. METHODS: We analyzed the prevalence and type of stroke/transient ischemic attack (TIA), factors associated with cerebrovascular ischemic events, and stroke-free survival in a large cohort fulfilling the American College of Rheumatology or Ishikawa criteria of TA. RESULTS: Among 320 patients with TA (median age at diagnosis, 36 [25-47] years; 261 [86%] women), 63 (20%) had a stroke (n=41; 65%) or TIA (n=22; 35%). Ischemic event localized in the carotid territory for 55 (87%) patients and the vertebral artery territory in 8 (13%) patients. Multiple stenosis were observed in 33 (52%) patients with a median number of stenosis of 2 (minimum, 0 to maximum, 11), and aneurysms were observed in 10 (16%) patients. A history of stroke or TIA before TA diagnosis (hazard ratio [HR], 4.50 [2.45-8.17]; P<0.0001), smoking (HR, 1.75 [1.01-3.02]; P=0.05), myocardial infarction history (HR, 0.21 [0.05-0.89]; P=0.039), thoracic aorta involvement (HR, 2.05 [1.30-3.75]; P=0.023), time from first symptoms to diagnosis >1 year (HR, 2.22 [1.30-3.80]; P=0.005), and aspirin treatment (HR, 1.82 [1.04-3.19]; P=0.035) were associated with cerebrovascular ischemic event. In multivariate analysis, time from first symptoms to TA diagnosis >1 year (HR, 2.16 [1.27-3.70]; P=0.007) was independently associated with cerebrovascular ischemic events in patients with TA. The HR for cerebrovascular ischemic event in patients who already experienced a stroke/TIA was 5.11 (2.91-8.99; P<0.0001), compared with those who had not. CONCLUSIONS: Carotid stroke/TIA is frequent in TA. We identified factors associated with cerebrovascular ischemic events.

A history of variceal bleeding is associated with further bleeding under atezolizumab-bevacizumab in patients with HCC.

BACKGROUND: Atezolizumab-bevacizumab is the new standard for advanced hepatocellular carcinoma (HCC) but its impact on portal hypertension (PHT) is unknown. We aimed to identify predictive factors of acute variceal bleeding (AVB) and to monitor PHT parameters under treatment. METHODS: We conducted a prospective study including all cirrhotic patients treated with atezolizumab-bevacizumab since 2020. We performed monitoring of PHT using upper endoscopy at inclusion and at 6 months and hepatic venous pressure gradient (HVPG) at inclusion, 3 and 6 months after the beginning of treatment. We also included a retrospective series of patients treated with sorafenib. Time-to-events data were estimated by Kaplan-Meier with the log-rank test, along with Cox models. RESULTS: Forty-three patients treated with atezolizumab-bevacizumab were included (male 79.1%, Child-Pugh A 86%). At baseline, 48.8% were treated with curative anticoagulation, 16.3% already experienced AVB and 25.6% had large oesophageal varices (EV). Sorafenib group characteristics were similar. Vascular invasion was present in 60.5% and median was HVPG 8.5 mm Hg. No significant modification in HVPG and EV size was observed at 6 months in the whole cohort but also when considering vascular invasion and radiological response. 14% presented AVB within a median time of occurrence of 3 months, without bleeding-related death. In multivariate analysis, history of AVB (HR = 10.58, p = .03) was associated with AVB. AVB incidence was higher in atezolizumab-bevacizumab compared to sorafenib group (21% vs. 5% at 1 year, p = .02). CONCLUSIONS: Atezolizumab-bevacizumab treatment was associated with a higher risk of AVB compared to sorafenib. A history of AVB was associated with AVB during follow-up, which questions the use of bevacizumab in this setting.

Systematic characterization of maturation time of fluorescent proteins in living cells.

The slow maturation time of fluorescent proteins (FPs) limits the temporal accuracy of measurements of rapid processes such as gene expression dynamics and effectively reduces fluorescence signal in growing cells. We used high-precision time-lapse microscopy to characterize the maturation kinetics of 50 FPs that span the visible spectrum at two different temperatures in Escherichia coli cells. We identified fast-maturing FPs from this set that yielded the highest signal-to-noise ratio and temporal resolution in individual growing cells.

High TG to HDL ratio plays a significant role on atherosclerosis extension in prediabetes and newly diagnosed type 2 diabetes subjects.

AIMS: We investigated the role of TG to HDL ratio (TG/HDL) on atherosclerosis extension, defined as presence of coronary artery calcium (CAC), carotid and femoral plaque, in prediabetes or newly diagnosed type 2 diabetes (T2D). METHODS: We performed a retrospective, cross-sectional, single centre study involving 440 prediabetes or newly diagnosed controlled T2D subjects. Participants underwent CAC analysis by computed tomography and carotid and femoral plaque evaluation by ultrasonography and were stratified in high TG/HDL (H-TG/HDL) or low TG/HDL (L-TG/HDL) group according to TG/HDL median value. We estimated atherosclerosis extension according to the number of involved vascular districts. RESULTS: CAC was higher in the H-TG/HDL group than L-TG/HDL group (29.15 [0.0-95.68] vs 0.0 [0.0-53.97] AU, P < .01) and CAC > 0 was more prevalent in the H-TG/HDL group than L-TG/HDL group (64.5% vs 45%, P < .001). Femoral atherosclerosis was higher in the H-TG/HDL group than L-TG/HDL group (57.3% vs 43.6%, P < .01). H-TG/HDL group exhibited a lower prevalence of subjects with 0-TWP compared to L-TG/HDL group (21.8% vs 38.6%, P < .01) and higher percentages of subjects with 2-TWP or 3-TWP than L-TG/HDL group (for 2-TWP 29.5% vs 21.5%, P < .05; for 3-TWP 32.7% vs 20.9%, P < .01). Multiple logistic regression analysis showed that a H-TG/HDL was inversely associated to 0-TWP (P < .05) and positively associated with 2-TWP (P < .05) and 3-TWP (P < .01). CONCLUSIONS: Our data suggest that TG/HDL is a marker of increased atherosclerotic extension in prediabetes and newly diagnosed T2D and may be useful to identify subjects with a higher cardiovascular risk profile.

Diabetic foot ulcer management in a multidisciplinary foot centre: one-year healing, amputation and mortality rate.

OBJECTIVE: To describe the rates of healing, major amputation and mortality after 12 months in patients with a new diabetic foot ulcer (DFU) and their care in a French diabetic foot service (DFS). METHOD: A prospective single-centre study including patients from March 2009 to December 2010. The length of time to healing, minor amputation, major amputation and mortality rate after inclusion were analysed using the Kaplan-Meier method. RESULTS: Some 347 patients were included (3% lost to follow-up), with a median follow-up (IQR) of 19 (12-24) months. The mean (SD) age was 65±12 years, 68% were male, and the median duration of the ulcer was 49 (19-120) days. Complications of the DFU were ischaemia (70%), infection (55%) and osteomyelitis (47%). Of the patients, 50% were inpatients in the DFS at inclusion (median duration of hospitalisation 26 (15-41) days). The rate of healing at one year was 67% (95% confidence interval (CI): 61-72); of major amputation 10% (95% CI: 7-17); of minor amputation 19% (95% CI: 14-25), and the death rate was 9% (95% CI: 7-13). Using an adjusted hazard ratio, the predictive factors of healing were perfusion and the area of the wound. The risk factors for a major amputation were active smoking and osteomyelitis. The risk factors for mortality were perfusion and age. CONCLUSION: This study confirms the need to treat DFUs rapidly, in a multidisciplinary DFS.

Relationship Among Fatty Liver, Specific and Multiple-Site Atherosclerosis, and 10-Year Framingham Score.

Despite a well-documented increase in the prevalence of subclinical atherosclerosis in patients with steatosis, the relationship among steatosis and atherosclerosis, specific atherosclerotic sites, multiple-site atherosclerosis, and cardiovascular risk prediction is incompletely understood. We studied the relationship among steatosis, atherosclerosis site, multiple-site atherosclerosis, coronary artery calcification (CAC), and 10-year Framingham Risk Score (FRS) in 2,554 patients with one or more cardiovascular risk factors (CVRF), free of cardiovascular events and other chronic liver diseases, and drinking less than 50 g alcohol/day. All patients underwent arterial ultrasound (carotid [CP] and femoral [FP] plaques defined as intima-media thickness (IMT) > 1.5 mm), coronary computed tomography scan (severe CAC if ≥ 100), 10-year FRS calculation, and steatosis detection by the fatty liver index (FLI, present if score ≥ 60). Patients with steatosis (36% of total) had higher prevalence of CP (50% versus 45%, P = 0.004) and higher CAC (181 ± 423 versus 114 ± 284, P < 0.001) but similar prevalence of FP (53% versus 50%, P = 0.099) than patients without steatosis. Steatosis was associated with carotid IMT and CAC, but not with FP, independent of age, diabetes, hypertension, and tobacco use (P < 0.001). Fifty-three percent of patients had at least 2-site atherosclerosis and steatosis was associated with at least 2-site atherosclerosis independent of age and CVRF (odds ratio = 1.21, 95% confidence interval 1.01-1.45, P = 0.035). Sixty-four percent of patients with steatosis had a FRS score of 10% or more. FLI was associated with FRS beyond the CVRF or the number of atherosclerosis sites (P < 0.001). Adding FLI to CVRF predicted an FRS greater than or equal to 10% better than CVRF alone (area under the receiver operating characteristic curve = 0.848 versus 0.768, P < 0.001). Conclusion: Steatosis is associated with carotid and coronary, but not femoral atherosclerosis, and with cardiovascular mortality risk. The multiple-site involvement and quantitative tonic relationship could reinforce the prediction of cardiovascular mortality or events over classical CVRF or imaging-based detection of atherosclerosis.

Circulating Receptor Activator of Nuclear Factor kB Ligand and triglycerides are associated with progression of lower limb arterial calcification in type 2 diabetes: a prospective, observational cohort study.

BACKGROUND: Lower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes. METHODS: Lower limb arterial calcification scores were determined by computed tomography at baseline and after a mean follow up of 31.20 ± 3.86 months. Serum RANKL (Receptor Activator of Nuclear factor kB Ligand) and bone remodeling, inflammatory and metabolic parameters were measured at baseline. The predictive effect of these markers on calcification progression was analyzed by a multivariate linear regression model. RESULTS: At baseline, mean ± SD and median lower limb arterial calcification scores were, 2364 ± 5613 and 527 respectively and at the end of the study, 3739 ± 6886 and 1355 respectively. Using multivariate analysis, the progression of lower limb arterial log calcification score was found to be associated with (ß coefficient [slope], 95% CI, p-value) baseline log(calcification score) (1.02, 1.00-1.04, p < 0.001), triglycerides (0.11, 0.03-0.20, p = 0.007), log(RANKL) (0.07, 0.02-0.11, p = 0.016), previous ischemic cardiomyopathy (0.36, 0.15-0.57, p = 0.001), statin use (0.39, 0.06-0.72, p = 0.023) and duration of follow up (0.04, 0.01-0.06, p = 0.004). CONCLUSION: In patients with type 2 diabetes, lower limb arterial calcification is frequent and can progress rapidly. Circulating RANKL and triglycerides are independently associated with this progression. These results open new therapeutic perspectives in peripheral diabetic calcifying arteriopathy. Trial registration NCT02431234.

Safety and effectiveness of transjugular renal biopsy for systemic lupus erythematosus and antiphospholipid antibody syndrome patients taking antithrombotics.

BACKGROUND: Renal biopsy is the cornerstone of systemic lupus erythematosus (SLE) nephritis and antiphospholipid syndrome (APS) nephropathy management. However, transcutaneous renal biopsy (TCRB) is hampered by the antithrombotic treatment frequently prescribed for those diseases. Transjugular renal biopsy (TJRB) offers an attractive alternative for patients at increased risk of bleeding. The primary objective of the study was to describe the safety profile and diagnostic performance of TJRB in SLE and APS patients. METHODS: All SLE and/or APS patients who underwent a renal biopsy in our department (between January 2004 and October 2016) were retrospectively reviewed. Major complications were death, haemostasis nephrectomy, renal artery embolization, red blood cell transfusion, sepsis and vascular thrombosis; macroscopic haematuria, symptomatic perirenal/retroperitoneal bleeding and renal arteriovenous fistula without artery embolization were considered as minor complications. RESULTS: Two hundred and fifty-six TJRBs-119 without antithrombotics (untreated), 69 under aspirin and 68 on anticoagulants and 54 TCRBs without antithrombotics-were analysed. Their major and minor complication rates, respectively, did not differ significantly for the four groups: 0 and 8% for untreated TJRBs, 1 and 6% for aspirin-treated, 6 and 10% for anticoagulant-treated and 2 and 2% for TCRBs. The number of glomeruli sampled and the biopsy contribution to establishing a histological diagnosis was similar for the four groups. CONCLUSIONS: TJRBs obtained from SLE and APS patients taking antithrombotics had diagnostic yields and safety profiles similar to those of untreated TCRBs. Thus, TJRB should be considered for SLE and APS patients at risk of bleeding.

Multiparametric Differentiation of Idiopathic Dilated Cardiomyopathy With and Without Congestive Heart Failure by Means of Cardiac and Hepatic T1-Weighted MRI Mapping.

OBJECTIVE. The purpose of this study was to test the hypothesis that patients with idiopathic dilated cardiomyopathy (IDCM) and heart failure have increased liver T1 relaxation times at MRI owing to congestion compared with the T1 relaxation times in patients with IDCM without heart failure and healthy control subjects. MATERIALS AND METHODS. For this retrospective cross-sectional study, 55 subjects (33 men, 22 women; mean age, 47 ± 15 years) who had undergone cardiac MRI were included: 20 healthy control subjects and 35 consecutively registered patients with IDCM. Twenty-one patients were hospitalized for acute heart failure, and 14 patients were in stable condition without heart failure. The performances of cardiac volume, left ventricular (LV) longitudinal strain, and ejection fraction (LVEF) in differentiating IDCM with and without heart failure were compared with myocardial and liver T1 relaxation times by means of Mann-Whitney U test and ROC analysis. RESULTS. The native T1 relaxation time of myocardium was significantly greater in patients with IDCM than in healthy control subjects (p < 0.001) but could not be used to differentiate between IDCM with and IDCM without heart failure (p = 0.653). Conversely, the native T1 relaxation time of liver was significantly greater in patients with IDCM and heart failure than in those without heart failure (p < 0.001). Native T1 relaxation time of liver was the overall best parameter for identifying the presence of heart failure in patients with IDCM (AUC, 0.96). It performed better than LVEF (AUC, 0.88) and global longitudinal LV strain (AUC, 0.85). CONCLUSION. Native T1 relaxation time of liver is an easily accessible and accurate noninvasive imaging marker of congestive heart failure in patients with IDCM. It can be measured on standard short-axis cardiac MRI T1-weighted maps and facilitates differentiating patients with IDCM with from those without heart failure more accurately than established functional parameters, such as LV volume, LVEF, and LV strain.

COVID-19-associated collapsing glomerulopathy: a report of two cases and literature review.

Nephrotic range proteinuria has been reported during the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease (COVID-19). However, the pathological mechanisms underlying this manifestation are unknown. In this article, we present two cases of collapsing glomerulopathy (CG) associated with acute tubular necrosis during the course of COVID-19, and review the literature for similar reports. In our two cases, as in the 14 cases reported so far, the patients were of African ancestry. The 14 patients assessed had an APOL1 high-risk genotype. At the end of the reported period, two patients had died and five patients were still requiring dialysis. The 16 cases detailed in the present report strongly argue in favour of a causal link between SARS-CoV-2 infection and the occurrence of CG in patients homozygous for APOL1 high-risk genotype for which the term COVID-associated nephropathy (COVIDAN) can be put forward.

Diabetic foot ulcer management in a multidisciplinary foot centre: one-year healing, amputation and mortality rate.

OBJECTIVE: To describe the rates of healing, major amputation and mortality after 12 months in patients with a new diabetic foot ulcer (DFU) and their care in a French diabetic foot service (DFS). METHOD: A prospective single-centre study including patients from March 2009 to December 2010. The length of time to healing, minor amputation, major amputation and mortality rate after inclusion were analysed using the Kaplan-Meier method. RESULTS: Some 347 patients were included (3% lost to follow-up), with a median follow-up (IQR) of 19 (12-24) months. The mean (SD) age was 65±12 years, 68% were male, and the median duration of the ulcer was 49 (19-120) days. Complications of the DFU were ischaemia (70%), infection (55%) and osteomyelitis (47%). Of the patients, 50% were inpatients in the DFS at inclusion (median duration of hospitalisation 26 (15-41) days). The rate of healing at one year was 67% (95% confidence interval (CI): 61-72); of major amputation 10% (95% CI: 7-17); of minor amputation 19% (95% CI: 14-25), and the death rate was 9% (95% CI: 7-13). Using an adjusted hazard ratio, the predictive factors of healing were perfusion and the area of the wound. The risk factors for a major amputation were active smoking and osteomyelitis. The risk factors for mortality were perfusion and age. CONCLUSION: This study confirms the need to treat DFUs rapidly, in a multidisciplinary DFS.

Transvenous Renal Biopsy of Critically Ill Patients: Safety and Diagnostic Yield.

OBJECTIVES: Transvenous renal biopsy is an alternative way to obtain kidney samples from patients with bleeding risk factors (e.g., antiplatelet therapy and anticoagulation or coagulation disorders). This study was undertaken to determine the safety and diagnostic yield of transvenous renal biopsy of critically ill patients. DESIGN: Monocenter, retrospective, observational cohort study. SETTING: A 26-bed French tertiary ICU. PATIENTS: All patients undergoing in-ICU transvenous renal biopsy between January 2002 and February 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty patients (male/female sex ratio, 0.95; mean ± SD age, 47.3 ± 18.3 yr) were included. A histologic diagnosis was obtained for 77 patients (96.3%), with acute tubular necrosis being the most frequent: 23 (29.9%). A potentially treatable cause was found for 47 patients (58.7%). The numbers of patients with 0, 1, 2, or 3 factors (i.e., antiplatelet therapy, thrombopenia [< 150 G/L], and preventive or curative anticoagulation) at the time of the biopsy were, respectively: seven (8.8%), 37 (46.2%), 31 (38.7%), and five (6.3%). Four (5%) and two (2.5%) patients, respectively, had renal hematoma and macroscopic hematuria; none required any specific treatment. Six patients (7.5%) died in-ICU, and 90-day mortality was 8 of 80 (10%). No death was related to transvenous renal biopsy, and median biopsy-to-death interval was 38 days (interquartile range, 19.7-86 d). CONCLUSIONS: Based on this cohort of ICU patients with acute kidney injury, transvenous renal biopsy was safe and obtained a high diagnostic yield for these selected critically ill patients, even in the presence of multiple bleeding risk factors.

Overall survival and mortality risk factors in Takayasu's arteritis: A multicenter study of 318 patients.

OBJECTIVE: To report the long term mortality in Takayasu arteritis (TA) and to identify prognosis factors. METHODS: We analyzed the causes of death and the factors associated with mortality in a cohort of 318 patients [median age at diagnosis was 36 [25-47] years and 276 (86%) patients were women] fulfilling American College of Rheumatology and/or Ishikawa criteria of TA. A prognostic score for death and vascular complications was elaborated based on a multivariate model. RESULTS: Among 318 TA patients, 16 (5%) died after a median [IQR] follow-up of 6.1 [2.8-13.0] years. The median age at death was 38 [25-47] years with 88% of women. Main causes of death included mesenteric ischemia (n = 4, 25%) and aortic aneurysm rupture (n = 4, 25%). The mortality rate at 5 and 10 years was of 1.9% and 3.9%, respectively. Caucasians (p = 0.049) and smokers (p = 0.002) TA patients were more likely to die. There was an increased mortality in TA (SMR with 95% confidence interval, 2.73 [1.69-4.22]) as compared to age and sex matched healthy controls. We defined high risk patients for death and vascular complications according to the presence of two of the following factors (i.e a progressive clinical course, thoracic aorta involvement and/or retinopathy). In the high risk TA group, the 5-year incidence of death and vascular complication was 48.5% compared to 21.6% (p = 0.001) in those with low risk. CONCLUSION: The overall mortality in our Takayasu cohort was 5% after a median follow-up of 6.1 years. We identified specific characteristics that distinguish TA patients at highest risk for death and vascular complications.

Comparison of MR T1 and T2 mapping parameters to characterize myocardial and skeletal muscle involvement in systemic idiopathic inflammatory myopathy (IIM).

OBJECTIVES: To compare the performance of magnetic resonance (MR) relaxometry parameters to discriminate myocardial and skeletal muscle inflammation in idiopathic inflammatory myopathy (IIM) patients from healthy controls. MATERIALS AND METHODS: For this retrospective case-control study, 20 consecutive IIM patients (54 ± 18 years, 11 females) with cardiac involvement (troponin level > 50 ng/l) and 20 healthy controls (47 ± 12 years, 9 females) were included. All patients without cardiac MR imaging < 2 weeks prior to the laboratory testings were excluded. T1/T2 relaxation times, as well as T1-derived extracellular volume (ECV), relative tissue T1 shortening ΔT1 = (native T1tissue-post contrast T1tissue)/native T1tissue), and enhancement fraction EHF = (native T1tissue-post contrast T1tissue)/(native T1blood-post contrast T1blood), were compared using Mann-Whitney U test and ROC analysis. RESULTS: All measured MR relaxometry parameters significantly discriminated IIM patients and healthy controls, except T2 in skeletal muscles and ECV in the myocardium. In skeletal muscles, post contrast T1 and T1-derived parameters showed the best performance to discriminate IIM patients from healthy controls (AUC = 0.98 for post contrast T1 and AUC 0.94-0.97 for T1-derived parameters). Inversely, in the myocardium, native T1 and T2 showed better diagnostic performance (AUC = 0.89) than post contrast T1 (AUC = 0.76), ECV (AUC = 0.58), ΔT1 (AUC = 0.80) and EHF (0.82). CONCLUSIONS: MR relaxometry parameters applied to the myocardium and skeletal muscles might be useful to separate IIM patients from healthy controls. However, different tissue composition and vascularization should be taken into account for their interpretation. ΔT1 and EHF may be simple alternatives to ECV in highly vascularized tissues such as the myocardium. KEY POINTS: • MR relaxometry parameters applied to the myocardium and skeletal muscles are highly useful to separate IIM patients from healthy controls. • Different tissue composition and vascularization should be taken into account for T1 and T2 mapping parameter interpretation. • ΔT1 and EHF may be simple alternatives to ECV in highly vascularized tissues such as the myocardium.

Hypoalphalipoproteinemia and BRAFV600E Mutation Are Major Predictors of Aortic Infiltration in the Erdheim-Chester Disease.

Objective- Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by the infiltration of multiple tissues with lipid-laden histiocytes. Cardiovascular involvement is frequent in ECD and leads to a severe prognosis. The objective of this study was to determine whether an alteration of lipid metabolism participates in the lipid accumulation in histiocytes and the cardiovascular involvement in ECD. Approach and Results- An analysis of plasma lipid levels indicated that male ECD patients carrying the BRAFV600E (B-Raf proto-oncogene, serine/threonine kinase) mutation exhibited hypoalphalipoproteinemia, as demonstrated by low plasma HDL-C (high-density lipoprotein cholesterol) levels. Capacity of sera from male BRAFV600E ECD patients to mediate free cholesterol efflux from human macrophages was reduced compared with control individuals. Cardiovascular involvement was detected in 84% of the ECD patients, and we reported that the presence of the BRAFV600E mutation and hypoalphalipoproteinemia is an independent determinant of aortic infiltration in ECD. Phenotyping of blood CD14+ cells, the precursors of histiocytes, enabled the identification of a specific inflammatory signature associated with aortic infiltration which was partially affected by the HDL phenotype. Finally, the treatment with vemurafenib, an inhibitor of the BRAFV600E mutation, restored the defective sera cholesterol efflux capacity and reduced the aortic infiltration. Conclusions- Our findings indicate that hypoalphalipoproteinemia in male ECD patients carrying the BRAFV600E mutation favors the formation of lipid-laden histiocytes. In addition, we identified the BRAF status and the HDL phenotype as independent determinants of the aortic involvement in ECD with a potential role of HDL in modulating the infiltration of blood CD14+ cells into the aorta.

Polyvascular subclinical atherosclerosis in familial hypercholesterolemia: The role of cholesterol burden and gender.

BACKGROUND AND AIM: Heterozygous familial hypercholesterolemia (HeFH) is a genetic disease characterized by a heterogeneous phenotype. The assessment of cardiovascular (CV) risk is challenging for HeFH. Cholesterol burden (CB) allows to estimate the lifelong exposure to high levels of cholesterol. The aim of this study was to analyze the distribution of subclinical atherosclerosis and the relationship between atherosclerosis and the CB in a sample of HeFH patients, focusing on sex-related differences. METHODS AND RESULTS: 154 asymptomatic HeFH subjects underwent coronary-artery-calcium score (CACs) and Doppler ultrasound of carotid and femoral arteries. Yearly lipid profiles and HeHF history were obtained from patients' files in order to calculate total CB. Atherosclerotic burden was defined by the presence of CACs > 0 or by the presence of carotid or femoral plaque. Study population was stratified according to gender. The prevalence of CAC, carotid and femoral atherosclerosis was of 62%, 55% and 56%, respectively. Coronary district was the least involved in women, who had a higher prevalence in carotid atherosclerosis. When two vascular districts were affected, women had an increased prevalence of femoral and carotid atherosclerosis whereas men had a higher prevalence of coronary and femoral atherosclerosis. CB correlated to the presence of atherosclerosis in any of the three vascular districts with a significant increasing trend depending on the number of affected areas. CONCLUSIONS: A polyvascular atherosclerotic burden is found in asymptomatic HeFH patients. Gender differences in the territory distribution were observed. The early and lasting exposure to high cholesterol, as expressed by CB, is a major determinant of atherosclerotic burden.