Interaction between poly(A)-binding protein PABPC4 and nuclear receptor corepressor NCoR1 modulates a metabolic stress response.

Mitochondria are organelles known primarily for generating ATP via the oxidative phosphorylation process. Environmental signals are sensed by whole organisms or cells and markedly affect this process, leading to alterations in gene transcription and, consequently, changes in mitochondrial function and biogenesis. The expression of mitochondrial genes is finely regulated by nuclear transcription factors, including nuclear receptors and their coregulators. Among the best-known coregulators is the nuclear receptor corepressor 1 (NCoR1). Muscle-specific knockout of NCoR1 in mice induces an oxidative phenotype, improving glucose and fatty acid metabolism. However, the mechanism by which NCoR1 is regulated remains elusive. In this work, we identified the poly(A)-binding protein 4 (PABPC4) as a new NCoR1 interactor. Unexpectedly, we found that silencing of PABPC4 induced an oxidative phenotype in both C2C12 and MEF cells, as indicated by increased oxygen consumption, mitochondria content, and reduced lactate production. Mechanistically, we demonstrated that PABPC4 silencing increased the ubiquitination and consequent degradation of NCoR1, leading to the derepression of PPAR-regulated genes. As a consequence, cells with PABPC4 silencing had a greater capacity to metabolize lipids, reduced intracellular lipid droplets, and reduced cell death. Interestingly, in conditions known to induce mitochondrial function and biogenesis, both mRNA expression and PABPC4 protein content were markedly reduced. Our study, therefore, suggests that the lowering of PABPC4 expression may represent an adaptive event required to induce mitochondrial activity in response to metabolic stress in skeletal muscle cells. As such, the NCoR1-PABPC4 interface might be a new road to the treatment of metabolic diseases.

Gynandromorphism in Amblyomma cajennense and Rhipicephalus sanguineus (Acari: Ixodidae).

During a survey of ticks on horses in November 2000, at the University of São Paulo farm in Pirassununga county, São Paulo, Brazil, 1 gynandromorph of Amblyomma cajennense was collected from a naturally infested horse. In another survey on dogs in March 2001, in the urban area of Monte Negro, Rondônia, Brazil, a gynandromorph of Rhipicephalus sanguineus was collected from a naturally infested dog. Both specimens are described and classified as perfect bipartite protogynanders.

Living morphogenesis of the ventricles and congenital pathology of their component parts.

Living morphogenetic studies show that each definitive ventricle is constructed from different primitive cardiac segments, and each has its specific anatomical features. These ventricular segments are the atrioventricular junction; the primitive inlet segment, part of the primary heart tube, which initially provides the inlets of each ventricle; the primitive outlet segment, which gives rise to both ventricular outlets; and the apical trabeculated regions of the right and left ventricles which grow from the primary heart tube, respectively. In this review, we describe regional pathology based on the relationship of these primitive ventricular components. We propose that the abnormal morphogenesis of one of these segments gives origin to regional ventricular pathology. For example, abnormal embryogenesis of the atrioventricular canal produces malformations of the atrioventricular junctions, such as double inlet ventricle, absence of one atrioventricular connection, and straddling and overriding atrioventricular valves. Similarly, abnormal morphogenesis of the primitive outlet segment gives rise to malformations of the subarterial region of each ventricle, along with the valves guarding these vessels. The principal anatomical features of these malformations of the ventricular inlets and outlets are described, and their possible morphogenesis is discussed. Due to the fact that the apical trabeculated region of each ventricle arises from a separate primitive segment, each ventricle can be identified according to the pattern of its apical trabeculations. This feature is crucial in the elucidation of complex congenital pathology, such as discordant atrioventricular connections.

Temporal and spatial asymmetries in the initial distribution of mesenchyme cells in the atrioventricular canal cushions of the developing chick heart.

BACKGROUND: We investigated potential early asymmetries in the distribution of mesenchymal cells within the inferior and superior AV cushions in the developing chick heart. METHODS: Chick embryos stages 16-20 HH were fixed, embedded in polyacrylamide, and the cell nuclei stained with propidium iodide. Cells counts were determined within the cardiac jelly of the atrioventricular canal (AV) by laser confocal microscopy in coronal planes spanning its entire length. RESULTS: Our data show at the different stages studied, 16-20 HH, that the inferior AV cushion invariably contains more cells than the superior AV cushion. In the inferior cushion, the cell distribution is bimodal, i.e., the proximal and distal regions have more mesenchymal cells than the middle part of the AV canal. In the superior cushion, there is a increasing gradient of mesenchymal cells along the longitudinal axis from the atrium to the ventricle. CONCLUSIONS: Our findings reveal that the temporal and spatial characteristics of mesenchyme formation in the inferior vs. superior AV cushion are different. This asymmetry suggests several potential hypotheses: (1) the distribution of the inducer molecule or its receptor has a distribution similar to that of mesenchymal cells, (2) the extracellular matrix has a differential composition or regionally-specific physical associations, (3) the endocardium is heterogeneous with respect to transformation capacity, or (4) these patterns result from an earlier inductive event. The potential importance of the observed asymmetries in the distribution of AV mesenchyme is discussed relative to localization patterns of molecules critical to successful cardiac morphogenesis and remodeling.

Primitive interventricular septum, its primordium, and its contribution in the definitive interventricular septum: in vivo labelling study in the chick embryo heart.

BACKGROUND: Because the studies on the embryological development of the primitive interventricular septum have been done with postmortem material, we do not know the site within the cardiac tube and the developmental stage at which the primordium appears and its anatomical manifestation in the mature heart. Consequently, we do not know its real contribution to the constitution of the definitive interventricular septum. METHODS: With this purpose, we selected an adequate biological model, the chick embryo heart and the in vivo labelling technique. We placed a label of gelatin India ink in the ventral fusion line of both cardiac primordia at the level of the interventricular grooves in the straight tube heart (stage 9+HH), and we traced the ink up to the mature heart (stage 36HH). We made histological sections of some hearts, of the zone where the label was found to investigate the first morphological manifestation of the primitive interventricular septum. We also made microdissections and scanning electron microscopic studies. RESULTS: The label placed at stage 9+HH in the ventral fusion line of both cardiac primordia, at the level of the interventricular grooves, was found at stage 14HH in the greater curvature of the looped heart, opposite the left interventricular groove. This label at stage 17HH was found in the apical trabecular region of the first cardiac septum (8-shaped septum) and in the mature heart (stage 36HH) in the definitive interventricular septum at the limit between the basal and the medial third of the definitive interventricular septum. CONCLUSIONS: Firstly, the primordium of the primitive interventricular septum appears at stage 9+HH, in the ventral fusion line of both cardiac primordia at the level of the interventricular grooves. Secondly, its first morphological manifestation takes place at stage 17HH, and it forms the apical trabeculated region of the first cardiac septum (8-shaped septum). Thirdly, the primitive interventricular septum gives origin to the middle and apical third of the definitive interventricular septum.

Coronary arteries in transposition of the great arteries.

The topic of coronary arteries in transposition of the great arteries (TGA) is complex and confusing despite having been the subject of several recently published reports. One hundred thirty-three autopsy specimens of uncomplicated TGA were studied, with special attention to methodologic issues in anatomic description and classification. Uncomplicated TGA was defined as congenital anomaly involving origin of the aorta from the right ventricle and of the pulmonary artery from the left ventricle. Three types of transposition were recognized ("anterior aorta," "side-by-side," and "posterior aorta") depending on the aortopulmonary relations, which were intrinsically defined by the relation of the valvular orifices of the great arteries with respect to the atrioventricular orifices. The frequency of distribution of individual coronary patterns differs substantially in the first 2 types of TGA. As in normal hearts, coronary arteries in TGA tend to originate from the facing sinuses (adjacent to the pulmonary valve); in TGA, however, variations in further distal anatomy are much more frequent. It is suggested that individual coronary patterns be described in terms of number of ostia, exact ostial location within or outside the aortic sinuses, and proximal course and distribution. The use of strict, simplified classifications of coronary patterns is discouraging because of the relevance of each individual anatomic parameter to clinical aims. Because of the aortopulmonary switch repair for TGA, this study emphasizes the surgical implications of the different coronary features.

Selectivity of human T lymphotropic virus type-1 (HTLV-1) and HTLV-2 infection among different populations in Brazil.

A seroprevalence study for human T lymphotropic virus type-1 (HTLV-1) and HTLV-2 was conducted in Sao Paulo, Brazil among 2,312 individuals that included following groups: 1,148 volunteer blood donors, 37 patients with tropical spastic paraparesis (TSP), 53 with lymphoproliferative disorders, 171 with a history of multiple blood transfusions, 268 human immunodeficiency virus type-1 (HIV-1) seropositive subjects, and 635 Amazonian Indians. Antibodies to HTLV-1/2 were screened by enzyme-linked immunosorbent assay (ELISA) and confirmed by Western blot and/or radioimmunoprecipitation. The differentiation of HTLV-1 and HTLV-2 was achieved using a synthetic recombinant peptide (rgp46) ELISA. We confirmed the presence of HTLV-1 infection in Brazil, both in blood donors (0.4%) and in patients exposed to blood transfusions (2.9%), as well as the occurrence of HTLV-1-associated TSP (11 patients, or 30% of all TSP cases) and adult T cell leukemia/lymphoma (two cases, or 3.5% of all hematologic malignancies). The HIV-1 infected individuals were shown to be coinfected (8.9%) with either HTLV-1 or HTLV-2. All HIV-1 and HTLV-2 coinfected individuals were intravenous drug abusers. In addition, we also demonstrated the presence of HTLV-2 (4.7%), and HTLV-1/2 (0.8%) in tribes of Amazonian Indians who lived in the eastern Amazon basin (southeastern State of Para). The selectivity of these retroviral infections in particular groups is emphasized, as well as the need for HTLV-1/2 screening of all blood donors in Brazil as a public health measure.

The right atrioventricular valvular apparatus in the chick heart.

The purpose of this study was to describe the detailed anatomy and histology of the right atrioventricular valve apparatus in the chicken. Newborn and adult chicken hearts were studied by anatomic description, light and scanning electron microscopy, and histologic (Masson's trichrome stain) and histochemical (Sirius Red stain) techniques. Our findings indicate the presence of an incomplete fibrous annulus, a great mural leaflet, and multiple microleaflets in the right atrioventricular apparatus of the chicken heart. The great mural leaflet, essentially muscular in structure, extended from the anterior and posterior juxtaseptal commissures and was subdivided into an anterior and a posterolateral region by the attachment of the anterolateral papillary muscle. The posterolateral region presented an intermediate cleft, subdividing this region into an anterior and a posterior portion. Multiple microleaflets, which adhered to the upper right side of the ventricular septum adjacent to the right atrioventricular orifice, inserted directly into the ventricular septum via short chordae tendineae, without papillary muscles. The microleaflets were composed of smooth subendocardial connective tissue, with varying amounts of type I, II and III collagen. In addition, we observed a central fibrous body, leading to fibrous continuity between the mitral and aortic valves and the mitral and right atrioventricular valves. An atrioventricular septum was also present.(ABSTRACT TRUNCATED AT 250 WORDS)

[Teratology and epidemiology in the study of environmental teratogens]. / La teratología y la epidemiología en el estudio de los teratógenos ambientales.

The processes of cellular migration, cellular differentiation and cellular multiplication are studied, since these are the basic developmental processes upon which teratogenic agents act resulting in congenital malformations. We also carefully analyze the interactions between teratogen-embryo in order to establish adequate parameters for analysis of environmental teratogens, as well as experimental teratogenesis and epidemiology. Information on the pathogenesis of congenital malformations obtained from experimental teratology in an adequate biological model, can be extrapolated to the human. The etiology of congenital malformations resulting from environmental teratogens can only be elucidated through epidemiology, since there is species specificity. Such a study must fulfill the following prerequisites: diagnosis of the congenital malformation, ruling out genetic factors in the family tree and determination of the exact time of exposure to the possible teratogen during the pregnancy.

The infundibular interrelationships and the ventriculoarterial connection in double outlet right ventricle. Clinical and surgical implications.

Fifty specimens of double outlet right ventricle were studied. The insertion of the outlet (infundibular) septum determines two types of infundibular interrelationships. In the first type, with anterior and posterior infundibulums, the outlet septum is inserted to the anterior limb of the septomarginal trabeculation; the posterior infundibulum is related with the atrioventricular orifices and the interventricular septum forms exclusively one of the walls of the posterior infundibulum. Therefore, the artery connected with the posterior infundibulum may be related with a subarterial ventricular septal defect. Of our material, 35 cases (70% of 50) had anterior and posterior infundibulums and, in 32, the aorta was connected with the posterior infundibulum (91.4% of 35). The ventricular septal defect was subaortic in 26 cases (81.2% of 32). In the second type, with side-by-side infundibulums, the outlet septum is inserted in to the ventriculo-infundibular fold in the proximity of the posterior limb of the septomarginal trabeculation. Both infundibulums are related with the atrioventricular orifices and the interventricular septum forms exclusively one of the walls of the medial infundibulum. Therefore, the artery connected with the medial infundibulum has the possibility of being related with a subarterial ventricular septal defect. Of our material, 13 cases (26% of 50) had side-by-side infundibulums. In all of these (100% of 13), the pulmonary trunk was connected with the medial infundibulum and the ventricular septal defect was subpulmonary in 12 cases (92.3% of 13). There were two cases (4% of 50) with a doubly committed ventricular septal defect. The insertion of the outlet septum permits one to determine the infundibular interrelationships, information which cannot be attained by taking into account the relationship of the great arteries with each other. Once the infundibular interrelationship is established, one must determine if the aorta is connected with the posterior or with the medial infundibulum, since, depending on the anatomical constitution of these infundibulums, there is the possibility of a ventricular septal defect being related with this artery. This information is indispensable before attempting the surgical correction of the double outlet right ventricle and it may be obtained by echocardiography or by angiocardiography.

Coronary arteries in truncus arteriosus.

The origin and distribution of the coronary arteries was described in 39 autopsy specimens of truncus arteriosus (TA). The specimens were classified according to the number and the patterns of the truncal cusps. The position of the truncal cusps was defined in relation to intracardiac structures, namely, the atrioventricular orifices. Bicuspid truncal valves were observed in 8 cases (21%), tricuspid in 22 cases (56%) and quadricuspid in 9 cases (23%). All tricuspid valves had 2 anterior and 1 posterior cusp. Great variability in the origin of the coronary arteries was observed, with a tendency for the right coronary artery to arise from the anterior right quadrant and for the left coronary artery to arise from the anterior and left quadrant. Such a tendency was observed in 50% of the bicuspid, in 59% of the tricuspid and in 66% of the quadricuspid valves. The anatomic right ventricle was always observed to be vascularized by a right coronary artery, and the anatomic left ventricle by a left coronary artery, even in cases in which there was a single coronary trunk. The anterior surface of the right ventricle was crossed by a right coronary artery in 5 cases. A single coronary artery was observed in 7 cases (18%). Embryologic considerations are offered, especially regarding the relation between the observed variability in coronary artery patterns in TA and the absence of the truncal septation.

[Embryologic and anatomic considerations on normal and pathologic heart separation. II. Atrioventricular and interventricular septum]. / Consideraciones embriológicas y anatómicas sobre la septación cardiaca normal y patológica. II. Septum atrioventricular e interventricular.

The atrioventricular septum is defined and its anatomical features are described. This consists of two regions, a muscular and a membranous region. Isolated atrioventricular types of defect are described. The normal and the pathological embryogenesis of the atrioventricular septum are discussed. A definition of the interventricular septum is given and its anatomical features are described. This septum is divided into two regions, a membranous and muscular region. The muscular region is divided into three regions: inflow region or inlet, trabeculated region and outflow region or outlet. Interventricular defects are classified according to the septal regions in which they are located. The anatomical features which characterize each type of interventricular septal defect are established. A brief comment on the normal and pathological morphogenesis of the interventricular septum is made.

[Embryologic and anatomic considerations on the normal and pathologic formation of the cardiac septum. I. Interauricular septum]. / Consideraciones embriológicas y anatómicas sobre la septación cardiaca normal y patológica. I. Septum interauricular.

A brief presentation of the normal embryological development of the human interatrial septum is made. The anatomical expression of each of its embryological components is described. Our classification of interatrial septal defect is enriched by their more precise anatomical description and by making a more correct morphogenetic interpretation, based on new information obtained by means of experimental embryology. Emphasis is made that absence of the interatrial septum does not preclude the diagnosis of viscero-atrial situs.

The contribution of the inferior endocardial cushion of the atrioventricular canal to cardiac septation and to the development of the atrioventricular valves: study in the chick embryo.

The contribution of the inferior endocardial cushion of the atrioventricular canal to cardiac septation and to the development of the atrioventricular valves was studied in the chick embryo by in vivo labelling techniques. The study was performed in White Leghorn chick embryos in which the dorsal cushion was labelled at stage 20-21 (Hamburger and Hamilton, 1951), when the endocardial cushions were not yet fused. The embryos were sacrificed at stage 35 (mature heart). These experiments allow us to conclude that the inferior atrioventricular cushion gives origin to: a) that part of the cardiac septum between the septal insertion of the antero-septal leaflet of the mitral valve and the fibrous ridge which is the equivalent to the human septal leaflet of the tricuspid valve (atrioventricular septum); b) the region of the interatrial and the interventricular septa adjacent to the atrioventricular septum; c) the portion of the antero-septal leaflet of the mitral valve which inserts into the septum; d) the fibrous ridge corresponding to the septal leaflet of the tricuspid valve. Microdissection shows that, when they appear at stage 18, the superior and inferior endocardial cushions of the atrioventricular canal are in continuity, without boundaries, with both the interatrial and interventricular septa. Therefore, each atrioventricular orifice opens into its corresponding ventricle, there being no stage in the development of the chick embryo heart in which the atrioventricular orifices are connected to the left ventricle at the same time. The development of the atrioventricular canal is similar in the chick and human.

Double outlet right ventricle: experimental morphogenesis in the chick embryo heart.

Double outlet right ventricle (DORV) was produced experimentally in the chick embryo by preventing the incorporation of the posteromedial conus into the left ventricle. This was accomplished by placing a ligature around the caudal end of the conus at a stage in which it is exclusively continuous with the right ventricle. The embryos were divided into two groups according to the stage of development of the conal ridge. In one group, the conal ridges had not appeared (stages 17-18); in the other they had begun to develop (stage 22). Both groups were divided into two subgroups; in one the ligature was left in place up to the mature heart stage and in the other it remained for only 24 hours. In all the embryos where the ligature remained until the mature heart stage a DORV was obtained, while in the embryos where the ligature remained in place for only 24 hours a DORV was obtained in only two-thirds of the cases. Two different types of DORV were produced: 1) with anterior and posterior infundibula in which the subpulmonary infundibulum was anterior to the subaortic infundibulum and there was a subaortic infracristal ventricular septal defect (VSD); 2) with side-by-side infundibula in which the subpulmonary infundibulum was on the left side and the subaortic infundibulum on the right side; the VSD was far from both infundibula. Our experiments show that DORV is an essentially infundibular malformation. In DORV there are two types of infundibular relationships: a) with anterior and posterior infundibula, and b) with side-by-side infundibula. The crista supraventricularis in the normal heart and the infundibular septum in DORV are two different anatomic and embryologic structures.