Whole-organism clone tracing using single-cell sequencing.

Embryonic development is a crucial period in the life of a multicellular organism, during which limited sets of embryonic progenitors produce all cells in the adult body. Determining which fate these progenitors acquire in adult tissues requires the simultaneous measurement of clonal history and cell identity at single-cell resolution, which has been a major challenge. Clonal history has traditionally been investigated by microscopically tracking cells during development, monitoring the heritable expression of genetically encoded fluorescent proteins and, more recently, using next-generation sequencing technologies that exploit somatic mutations, microsatellite instability, transposon tagging, viral barcoding, CRISPR-Cas9 genome editing and Cre-loxP recombination. Single-cell transcriptomics provides a powerful platform for unbiased cell-type classification. Here we present ScarTrace, a single-cell sequencing strategy that enables the simultaneous quantification of clonal history and cell type for thousands of cells obtained from different organs of the adult zebrafish. Using ScarTrace, we show that a small set of multipotent embryonic progenitors generate all haematopoietic cells in the kidney marrow, and that many progenitors produce specific cell types in the eyes and brain. In addition, we study when embryonic progenitors commit to the left or right eye. ScarTrace reveals that epidermal and mesenchymal cells in the caudal fin arise from the same progenitors, and that osteoblast-restricted precursors can produce mesenchymal cells during regeneration. Furthermore, we identify resident immune cells in the fin with a distinct clonal origin from other blood cell types. We envision that similar approaches will have major applications in other experimental systems, in which the matching of embryonic clonal origin to adult cell type will ultimately allow reconstruction of how the adult body is built from a single cell.

Neuromesodermal progenitors are a conserved source of spinal cord with divergent growth dynamics.

During gastrulation, embryonic cells become specified into distinct germ layers. In mouse, this continues throughout somitogenesis from a population of bipotent stem cells called neuromesodermal progenitors (NMps). However, the degree of self-renewal associated with NMps in the fast-developing zebrafish embryo is unclear. Using a genetic clone-tracing method, we labelled early embryonic progenitors and found a strong clonal similarity between spinal cord and mesoderm tissues. We followed individual cell lineages using light-sheet imaging, revealing a common neuromesodermal lineage contribution to a subset of spinal cord tissue across the anterior-posterior body axis. An initial population subdivides at mid-gastrula stages and is directly allocated to neural and mesodermal compartments during gastrulation. A second population in the tailbud undergoes delayed allocation to contribute to the neural and mesodermal compartment only at late somitogenesis. Cell tracking and retrospective cell fate assignment at late somitogenesis stages reveal these cells to be a collection of mono-fated progenitors. Our results suggest that NMps are a conserved population of bipotential progenitors, the lineage of which varies in a species-specific manner due to vastly different rates of differentiation and growth.

Mechanisms and Genetic Susceptibility of Chemotherapy-Induced Cardiotoxicity in Patients With Breast Cancer.

BACKGROUND: Cardiotoxicity remains an important adverse reaction of chemotherapy used in the treatment of breast cancer, leading to increased morbidity and mortality. DATA SOURCES: Anthracyclines, taxanes, and trastuzumab are the most commonly used cytotoxic drugs for the treatment of breast cancer. Cardiotoxicity may vary from asymptomatic forms to irreducible heart failure and death. AREAS OF UNCERTAINTY: Susceptibility for the occurrence of chemotherapy-induced cardiotoxicity and treatment resistance is multifactorial, with interindividual variability, determined by the interaction between genetic and phenotypic factors. Implementation of pharmacogenomic findings into clinical practice might be useful, to predict cardiotoxicity and to allow appropriate therapeutic measures. RESULTS AND CONCLUSIONS: This review will summarize the cellular mechanisms of chemotherapy-induced cardiotoxicity in breast cancer patients and will discuss the role of the genetic susceptibility for cardiac dysfunction.

Comparison of pulse wave velocity assessed by three different techniques: Arteriograph, Complior, and Echo-tracking.

Arterial stiffness estimated by pulse wave velocity (PWV) is an independent predictor of cardiovascular morbidity and mortality. Although recommended by the current guidelines, clinical applicability of this parameter is difficult, due to differences between the various techniques used to measure it and to biological variability. Our aim was to compare PWV assessed by 3 different commercially available systems. 100 subjects (51 ± 16 years, 45 men) were evaluated using the 3 methods: an oscillometric technique (Arteriograph, PWV-A); a piezo-electric method (Complior, PWV-C); and an high-resolution ultrasound technique implemented with an Echo-tracking system (Aloka, PWV-E). Conventional biological markers were measured. Correlations of PWV measured by the 3 methods were poor (r = 0.39, r = 0.39, and r = 0.31 for PWV-A vs. PWV-C, PWV-A vs. PWV-E, and PWV-C vs. PWV-E, respectively, all p < 0.05). By Bland-Altman analysis, mean difference (±SD) of PWV-A vs. PWV-C was -1.9 ± 2.0 m/s, of PWV-A vs. PWV-E -3.6 ± 1.9 m/s, and of PWV-C vs. PWV-E -2.7 ± 1.9 m/s, with a wide coefficient of variation (22.3, 25.7, and 25.7 %, respectively). As expected, PWV-A, PWV-C, and PWV-E correlated with other arterial stiffness parameters, such as intima-media thickness (r = 0.22, r = 0.22, and r = 0.36, respectively), E p (r = 0.37, r = 0.26, and r = 0.94, respectively), and augmentation index measured by Arteriograph method (r = 0.66, r = 0.35, and r = 0.26, respectively); all p < 0.05. Assessment of PWV is markedly dependent on the technique used to measure it, related to various methods for measuring traveled distance of the arterial wave. Our results suggest the urgent need to establish reference values of PWV for each of these techniques, separately, to be used in routine clinical practice.

The effect of indapamide versus hydrochlorothiazide on ventricular and arterial function in patients with hypertension and diabetes: results of a randomized trial.

OBJECTIVE: The objective of this study is to compare the effects of 2 types of diuretics, indapamide and hydrochlorothiazide, added to an angiotensin-converting enzyme inhibitor, on ventricular and arterial functions in patients with hypertension and diabetes. METHODS: This is a prospective, randomized, active-controlled, PROBE design study in 56 patients (57 ± 9 years, 52% men) with mild-to-moderate hypertension and type 2 diabetes, with normal ejection fraction, randomized to either indapamide (1.5 mg Slow Release (SR)/day) or hydrochlorothiazide (25 mg/d), added to quinapril (10-40 mg/d). All patients had conventional, tissue Doppler and speckle tracking echocardiography and assessment of endothelial and arterial functions and biomarkers, at baseline and after 6 months. RESULTS: Baseline characteristics were similar between groups; systolic and diastolic blood pressures decreased similarly, by 15% and 9% on indapamide and by 17% and 10% on hydrochlorothiazide (P < .05). Mean longitudinal systolic velocity and longitudinal strain increased by 7% and 14% on indapamide (from 5.6 ± 1.8 to 6.0 ± 1.1 cm/s and from 16.2% ± 1.8% to 18.5% ± 1.1%, both P < .05), but did not change on hydrochlorothiazide (P < .05 for intergroup differences), whereas ejection fraction and radial systolic function did not change. Similarly, mean longitudinal early diastolic velocity increased by 31% on indapamide (P < .05), but did not change on hydrochlorothiazide (P < .05 for intergroup differences). These changes were associated with improved endothelial and arterial functions on indapamide, but not on hydrochlorothiazide. CONCLUSION: Indapamide was found to improve measures of endothelial and arterial functions and to increase longitudinal left ventricular function compared with hydrochlorothiazide in patients with hypertension and diabetes, after 6 months of treatment. This study suggests that indapamide, a thiazide-like diuretic, has important vascular effects that can improve ventriculoarterial coupling.

Comparative reproducibility of the noninvasive ultrasound methods for the assessment of vascular function.

The aim of this work was to assess the reproducibility of ultrasound parameters of vascular function, since these measurements are currently recommended by the guidelines for the evaluation of the cardiovascular risk. Twenty subjects (51 ± 17 years, 11 men) had vascular ultrasound (Aloka Prosound α10) performed by two observers, at the level of the right common carotid artery for assessment of intima-media thickness (IMT), "wall tracking", and "wave-intensity analysis", and at the level of the right brachial artery for the assessment of flow-mediated dilation (FMD). Wave intensity is a hemodynamic index, evaluating ventriculo-arterial interaction and can be measured in real time by a double-beam ultrasound technique through simultaneous recording of carotid arterial blood flow velocity and diameter. Carotido-femoral pulse wave velocity (PWV) was determined using the Complior method. Intra- and inter-observer reproducibility was assessed during a first session, when three consecutive acquisitions were made (first observer → second observer → first observer); repeatability was evaluated 1 week later (second observer). The most reproducible and repeatable parameters were PWV (intraobserver ±3.3%, interobserver ±2.6%, repeatability ±5.6%) and IMT (±3.7, ±4.3, ±4.9%, respectively). Intraobserver reproducibility for arterial stiffness and ventriculo-arterial coupling parameters was the highest for the beta index (±3.8%), and the lowest for the second systolic peak (±22.4%). Interobserver reproducibility and repeatability varied between very good for the wave speed (±5.5 and ±4.3%), and unsatisfactory for the negative area (±31.8 and ±38.6%). FMD had good reproducibility (intraobserver ±11.6%, interobserver ±8%, repeatability ±7%), whereas augmentation index had only satisfactory results (±17.8, ±8.4, ±23.8%, respectively). Only some parameters of vascular function have good reproducibility and repeatability, better or similar to other ultrasound methods and, therefore, these are ready to be used in routine clinical practice.

scChIX-seq infers dynamic relationships between histone modifications in single cells.

Regulation of chromatin states involves the dynamic interplay between different histone modifications to control gene expression. Recent advances have enabled mapping of histone marks in single cells, but most methods are constrained to profile only one histone mark per cell. Here, we present an integrated experimental and computational framework, scChIX-seq (single-cell chromatin immunocleavage and unmixing sequencing), to map several histone marks in single cells. scChIX-seq multiplexes two histone marks together in single cells, then computationally deconvolves the signal using training data from respective histone mark profiles. This framework learns the cell-type-specific correlation structure between histone marks, and therefore does not require a priori assumptions of their genomic distributions. Using scChIX-seq, we demonstrate multimodal analysis of histone marks in single cells across a range of mark combinations. Modeling dynamics of in vitro macrophage differentiation enables integrated analysis of chromatin velocity. Overall, scChIX-seq unlocks systematic interrogation of the interplay between histone modifications in single cells.

Single-cell sortChIC identifies hierarchical chromatin dynamics during hematopoiesis.

Post-translational histone modifications modulate chromatin activity to affect gene expression. How chromatin states underlie lineage choice in single cells is relatively unexplored. We develop sort-assisted single-cell chromatin immunocleavage (sortChIC) and map active (H3K4me1 and H3K4me3) and repressive (H3K27me3 and H3K9me3) histone modifications in the mouse bone marrow. During differentiation, hematopoietic stem and progenitor cells (HSPCs) acquire active chromatin states mediated by cell-type-specifying transcription factors, which are unique for each lineage. By contrast, most alterations in repressive marks during differentiation occur independent of the final cell type. Chromatin trajectory analysis shows that lineage choice at the chromatin level occurs at the progenitor stage. Joint profiling of H3K4me1 and H3K9me3 demonstrates that cell types within the myeloid lineage have distinct active chromatin but share similar myeloid-specific heterochromatin states. This implies a hierarchical regulation of chromatin during hematopoiesis: heterochromatin dynamics distinguish differentiation trajectories and lineages, while euchromatin dynamics reflect cell types within lineages.

Myocardial systolic velocities and deformation assessed by speckle tracking for early detection of left ventricular dysfunction in asymptomatic patients with severe primary mitral regurgitation.

AIMS: In asymptomatic patients with severe primary mitral regurgitation (PMR), early detection of left ventricular (LV) dysfunction indicates the optimal timing of mitral valve surgery; however, normal ejection fraction (EF) and end-systolic diameter (ESD) can mask significant LV impairment. METHODS: We studied 28 asymptomatic patients (59 ± 13 years, 18 male) with severe PMR, EF > 60%, and ESD < 45 mm, and 10 age-matched healthy subjects. All underwent echocardiography with tissue velocity imaging to assess LV geometry, EF, and longitudinal systolic function; and two-dimensional speckle tracking to assess longitudinal strain (LS) and longitudinal strain rate (LSR), and radial strain (RS) and radial strain rate (RSR). Patients were reevaluated 14 days after successful mitral valve repair and divided in: IA, with a postoperative EF reduction >10% (13 patients) and IB, with an EF reduction <10% (15 patients). RESULTS: Patients with PMR had longitudinal dysfunction and decreased radial systolic deformation, by comparison with controls, although EF and ESD were similar. Subgroup IA had significantly lower S(TVI) , LS, and RS than IB (7.3 ± 0.9 vs 10.8 ± 1.5 m/s; -16.0 ± 4.2% vs -21.7 ± 2.1%; and 37.4 ± 2.5% vs 41.6 ± 2.4%; all p < 0.001) although preoperative LV mass index, LV diameters, and EF were similar. Multiple stepwise regression analysis showed that S(TVI) and the combination of S(TVI) and LS represent the main independent predictors for a postoperative EF reduction >10% (r(2) = 0.52, p < 0.001; and r(2) = 0.70, p < 0.001, respectively). CONCLUSION: Myocardial systolic velocities as well as radial and longitudinal LV deformation assessed by speckle tracking can detect subclinical LV dysfunction and predict impaired postoperative LV function in asymptomatic patients with severe PMR.

Psychological Variables Explaining the Students' Self-Perceived Well-Being in University, During the Pandemic.

Introduction: In the coronavirus disease 2019 (COVID-19) pandemic, Romanian universities switched to emergency relocation and online education, with students experiencing a sense of isolation, which affected their well-being, pace and normal learning style, relationships with other colleagues, and Professors. Beyond the technological obstacles that have arisen in learning, the aim of this study is to highlight the psychological variables that are associated and that explain the self-perceived well-being of students, in university, in the pandemic. The psychological variables studied were the following: the level of openness and personal autonomy, as personality traits of students but also the mechanisms for regulating their academic motivation. Method: We used a questionnaire-based survey, wherein all four research instruments had been validated and adapted to the investigated population. The subjects were BA and MA students at the University of Oradea, Romania (N = 150), the majority being females (95.5%) with the age range of 27 years old. Pearson Correlation and Multiple Linear Regression were used to test the two hypotheses. Results: Research data obtained in the correlation analysis, point out association relationships with moderate and high effects size, between positive attitude toward self, others and student life and: openness to learning, openness to aesthetics, behavioral autonomy, cognitive autonomy, intrinsic motivation, and identification motivation. Furthermore, in regression analysis, it was revealed that regarding the variance of results concerning students' self-perceived well-being in university (positive attitude toward oneself, others, and student life), it contributes both of students' personality traits (such as openness and personal autonomy) and their intrinsic motivation and identification motivation. Conclusion: The fundamental conclusion of the research is that, although the personality traits of students explain in a higher percentage the variability of results in students' self-perceived well-being (in terms of positive attitude toward self, others, and student life), motivation regulation mechanisms play an important role, especially in the conditions of online activities. The results have direct implications for the work carried out in universities. The educational policies developed by specialists and government will have to emphasize the ways of forming resilient student communities in periods of sudden transition and adaptation to change which take place in education and society.

"Supranormal" cardiac function in athletes related to better arterial and endothelial function.

OBJECTIVE: Athlete's heart is associated with left ventricular (LV) hypertrophy (LVH), and "supranormal" cardiac function, suggesting that this is a physiological process. Hypertrophy alone cannot explain increase in cardiac function, therefore, other mechanisms, such as better ventriculo-arterial coupling might be involved. METHODS: We studied 60 male (21 +/- 3 years) subjects: 27 endurance athletes, and a control group of 33 age-matched sedentary subjects. We assessed global systolic and diastolic LV function, short- and long-axis myocardial velocities, arterial structure and function and ventriculo-arterial coupling, endothelial function by flow-mediated dilatation, and amino-terminal pro-brain natriuretic peptide (NT-proBNP) and biological markers of myocardial fibrosis and of oxidative stress. RESULTS: Athletes had "supranormal" LV longitudinal function (12.4 +/- 1.0 vs 10.1 +/- 1.4 cm/s for longitudinal systolic velocity, and 17.4 +/- 2.6 vs 15.1 +/- 2.4 cm/s for longitudinal early diastolic velocity, both P < 0.01), whereas ejection fraction and short-axis function were similar to controls. Meanwhile, they had better endothelial function (16.7 +/- 7.0 vs 13.3 +/- 5.3%, P < 0.05) and lower arterial stiffness (pulse wave velocity 7.1 +/- 0.6 vs 8.8 +/- 1.1 m/s, P = 0.0001), related to lower oxidative stress (0.259 +/- 0.71 vs 0.428 +/- 0.88 nmol/mL, P = 0.0001), with improved ventriculo-arterial coupling (37.1 +/- 21.5 vs 15.5 +/- 13.4 mmHg.m/s(3)x 10(3), P = 0.0001). NT-proBNP and markers of myocardial fibrosis were not different from controls. LV longitudinal function was directly related to ventriculo-arterial coupling, and inversely related to arterial stiffness and to oxidative stress. CONCLUSIONS: "Supranormal" cardiac function in athletes is due to better endothelial and arterial function, related to lower oxidative stress, with optimized ventriculo-arterial coupling; athlete's heart is purely a physiological phenomenon, associated with "supranormal" cardiac function, and there are no markers of myocardial fibrosis.

3D echocardiography, arterial stiffness, and biomarkers in early diagnosis and prediction of CHOP-induced cardiotoxicity in non-Hodgkin's lymphoma.

CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) represents standard chemotherapy in non-Hodgkin's lymphoma (NHL) with risk of cardiotoxicity. To define new parameters, such as 3D myocardial deformation, arterial stiffness, and biomarkers for early diagnosis and prediction of cardiotoxicity. 110 NHL patients with LVEF > 50%, scheduled for CHOP, were evaluated at baseline, after third cycle and chemotherapy completion. 3DE assessed LVEF and myocardial deformation: longitudinal (LS), radial, circumferential, area strain. Echo-tracking analysed arterial stiffness: PWV, ß index, wave intensity. Troponin I and NT-pro-BNP were measured. After chemotherapy completion, 18 patients (16%) (group I) developed cardiotoxicity (LVEF decrease < 50%, with > 10% from baseline); 92 patients (group II) did not. Significant reduction of 3D LV deformation and increase of arterial stiffness developed starting with third cycle, with greater changes in group I. LS reduction and PWV increase after third cycle were the best independent predictors for LVEF decrease; the association of LS decrease by > 19% and PWV increase by > 27% after third cycle predicted cardiotoxicity after chemotherapy completion (90% sensitivity and 81% specificity). 3D LS and PWV can detect early chemotherapy-induced cardiotoxicity and predict LVEF decline. These parameters should be incorporated in clinical protocols to monitor cardiovascular function during chemotherapy and early intervention.

Eleven grand challenges in single-cell data science.

The recent boom in microfluidics and combinatorial indexing strategies, combined with low sequencing costs, has empowered single-cell sequencing technology. Thousands-or even millions-of cells analyzed in a single experiment amount to a data revolution in single-cell biology and pose unique data science problems. Here, we outline eleven challenges that will be central to bringing this emerging field of single-cell data science forward. For each challenge, we highlight motivating research questions, review prior work, and formulate open problems. This compendium is for established researchers, newcomers, and students alike, highlighting interesting and rewarding problems for the coming years.

Aorto-pulmonary fistula as a late complication of multiple valve replacement after Streptococcus Bovis endocarditis in a patient with occult colon carcinoma.

We report a case of aorto-pulmonary fistula following multiple valve surgery in a patient with colon carcinoma who had had recurrent episodes of Streptococcus Bovis endocarditis. Diagnosis was made by transesophageal echocardiography and aortography. Patient underwent emergency percutaneous implantation of an aortic endoprosthesis, but he continued to deteriorate and the fatal outcome could not be changed. This case underscores the importance of examination of gastrointestinal tract in patients with Streptococcus Bovis endocarditis.

Impaired Cardiac Function in Patients with Multiple Sclerosis by Comparison with Normal Subjects.

Multiple sclerosis (MS), neurologic disease affecting young population, may cause cardiovascular dysfunction, due to autonomous nervous dysfunction, physical invalidity, increased oxidative stress, and systemic inflammatory status. However, cardiovascular function is rarely evaluated in these patients. We assessed left and right ventricular (LV and RV) function by 2D, 3D, tissue Doppler, and speckle tracking echocardiography, and vascular function by remodeling, stiffness, and endothelial dysfunction parameters in patients with MS, compared to control subjects. 103 subjects (35 ± 10 years,70 women) were studied: 67 patients with MS and 36 control subjects. Patients with MS had decreased LV systolic function, confirmed by lower 2D and 3D ejection fraction, mitral annular plane systolic excursion, longitudinal myocardial systolic velocities, and 2D and 3D global longitudinal strain. The RV function was also decreased, as demonstrated by lower fractional area change, tricuspid annular plane systolic excursion, longitudinal systolic velocities, and longitudinal strain. Additionally, LV diastolic and left atrial (LA)  function were decreased compared to controls. The parameters of arterial and endothelial function were similar between groups. Patients with MS have impaired biventricular function by comparison with normal subjects, with reduced LA function, but normal arterial and endothelial function. The noninvasive echocardiographic techniques might help to determine patients with MS at risk of developing cardiovascular dysfunction.

The Relationship of Carotid Arterial Stiffness and Left Ventricular Concentric Hypertrophy in Hypertension.

BACKGROUND: Left ventricular hypertrophy (LVH) and geometry patterns vary in different hemodynamic profiles The concentric hypertrophy (CH) pattern has been proved to have the worst prognosis. OBJECTIVES: The aim of the study was to test the hypothesis that carotid artery stiffness, as a marker of vascular damage, is associated with CH, independently of other potential determinants such as demographic factors (age, sex, BMI), clinical parameters (smoking, diabetes, creatinine level) and hemodynamic variables (blood pressure, pulse pressure [PP]). MATERIAL AND METHODS: The study involved 262 subjects (89 men): 202 patients with hypertension (153 untreated, 49 on medication), aged 55.7 ± 10 years, and 60 age-matched normal controls. The subjects were examined by echocardiography and carotid ultrasound with a high-resolution echo-tracking system. Based on the left ventricular mass index (LVMI) and relative wall thickness (RWT), the patients with hypertension were divided into four patterns of LVH and geometry: normal geometry (N, n = 57), concentric remodeling (CR, n = 48), concentric hypertrophy CH (n = 62) and eccentric hypertrophy (EH, n = 35). Intima-media thickness (IMT) and the parameters of arterial stiffness were also assessed using the ß stiffness index (ß), Young elastic modulus (Ep), arterial compliance (AC), one-point pulse wave velocity (PWVß) and the wave reflection augmentation index (AI). RESULTS: Univariate analysis showed that the following variables are significant in determining CH: ß > 8.4, Ep > 136 kPa, PWVß > 7.1 m/s, AI > 21.9%, systolic BP > 151 mm Hg, PP > 54, IMT > 0.56 and the presence of diabetes. However, by multivariate analysis only AI (OR 3.65, p = 0.003), PWVß > 7.1 m/s (OR 2.86, p = 0.014), systolic BP (OR 3.12, p = 0037) and the presence of diabetes (OR 3.75, p = 0.007) were associated independently with the occurrence of CH. CONCLUSIONS: Concentric hypertrophy in hypertension is strongly associated with carotid arterial stiffness and wave reflection parameters, independently of the influence of systolic blood pressure and diabetes.

The Assessment of Subclinical Cardiovascular Dysfunction in Treated Rheumatoid Arthritis.

BACKGROUND AND PURPOSE: Rheumatoid arthritis (RA) causes frequently cardiovascular complications, probably determined by early atherosclerosis in connection to chronic systemic inflammation. Purpose of our study was to assess subclinical cardiac and vascular dysfunction, and to evaluate the mechanisms of ventriculo-arterial interaction, in patients with correctly treated RA vs. normal subjects. METHODS: We evaluated 46 subjects (55±10 years, 2 men): 29 patients with seropositive treated RA (mean duration of 11±9 years), without documented cardiovascular or pulmonary disease, and 17 control subjects, matched for age, sex, and distribution of conventional major risk factors. All RA patients were under long-term treatment (more than 6 months) with Methotrexat + Sulfasalasine (22 patients) or Methotrexat + Sulfasalasine + Infliximab (7 patients). We determined biomarkers of inflammation (P-selectin, interleukines 1, 6, 10, 18, seric amiloid A, á-TNF, ã-interferon, C-reactive protein, anti-oxidated LDL antibodies), myocardial fibrosis (â-crosslaps) and ventricular overload (BNP). We assessed the parameters of cardiac function by standard and tissue Doppler echocardiography, intima-media thickness and arterial stiffness by "e-tracking" and "wave intensity analysis" (at the level of the right carotid artery), endothelial function by flow mediated dilation (FMD), and carotid-femoral pulse wave velocity by the Complior method. RESULTS: Biological parameters of inflammation, markers of myocardial fibrosis and of ventricular overload were not different between the 2 study groups. Also, parameters of subclinical cardiac and vascular function were similar between the two groups. RA patients had subclinical RV dysfunction, correlated to the duration of the disease. They also tended to have higher values of systolic pulmonary artery pressure than normals. CONCLUSION: Correctly treated patients with RA, with controlled systemic inflammation, have normal LV, endothelial and arterial function. However, in the absence of documented pulmonary disease, they do have subclinical RV dysfunction, correlated with the duration of disease. This suggests an intrinsic RV myocardial involvement but, since pulmonary artery pressure was also higher, a secondary mechanism might be also involved.

Histopathologic aspects of the limited endometrial hyperplasias--a study concerning 149 cases.

This study concerns 147 cases of limited endometrial hyperplasia, diagnosed at patients between IV, V, VI and VII decades of life. Histopathologically, the aspects were of basal hyperplasia--40 cases and polyp hyperplasia--107 cases. The polyp-like hyperplasia was present at pre and postmenopausal patients. At the premenopausal patients the polyps were hormonally active: glandular, glandular-cystic and adenomatous type polyps. In contrast, the majority of the postmenopausal patients presented hormonally inactive polyps, like cystic atrophic or fibrous polyps. Modifying the prognosis of lesions, we took in consideration the morphologic changes associated with these lesions, like epithelial metaplasia or nuclear atypia.