Developmental biology. Antagonists on the left flank.
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Activins↗
Biomedical subjects
N A Brown
Publications and source records attributed to N A Brown.
Mechanisms of deficient cardiac septation in the mouse with trisomy 16.
It used to be thought that the atrioventricular septum was predominantly the product of the atrioventricular endocardial cushions. In a previous study, we have shown that multiple developmental primordia are of importance in its formation. With this in mind, we have evaluated cardiac morphogenesis in the mouse with trisomy 16, an animal model with a high incidence of atrioventricular septal defects. Normal and trisomic fetuses from an Rb(11.16)2H/Rb(16.17)7Bnr x C57BL/6J cross were collected on days 10 to 15 of gestation and examined by scanning electron microscopy and histological serial sectioning. No evidence was found to suggest that atrioventricular septal defect could be explained simply on the basis of "failure of fusion" between the atrioventricular endocardial cushions. Rather, our findings supported two other developmental elements as being important in the genesis of atrioventricular septal defect. The first is an alteration in the configuration of the heart tube, with inadequate remodeling of the inner heart curvature. This resulted in the failure of the atrioventricular junction to expand to the right, with subsequent malalignment of the atrioventricular endocardial cushions with the proximal outflow cushions. The second is a variability in the connection of the primary atrial cardiac segment to the body of the embryo, the so-called dorsal mesocardium, which influences its relationship to the extracardiac mediastinal mesoderm. There appeared little difference in the connection between normal and trisomic embryos at the stage of 20 to 25 somites, but the area subsequently showed marked changes. In most trisomic embryos, the connection with the mediastinal mesoderm of the body was over a larger area than seen in normal embryos. As this area of attachment encloses the pulmonary pit, the entry point of the pulmonary vein, this gives potential for variation in the connection of the pulmonary vein. In addition, in the majority of trisomic embryos, the right pulmonary ridge (the spina vestibuli) did not accumulate extracardiac mesoderm, nor did it undergo the pronounced forward growth seen in normal embryos of equivalent stages. Consequently, the trisomic embryos show incomplete formation of both the atrial and the atrioventricular septal structures.
Animals↗
Embryonic asymmetry: the left side gets all the best genes.
The origin of left-right developmental asymmetry is a continuing puzzle, but some recent results provide new insights into the steps leading to organ asymmetry - implicating the homeobox protein Pitz-2 in one key step - and others support a model of symmetry-breaking that involves the chirality of microtubules.
Animals↗
Mechanism of hyperthermia effects on CNS development: rostral gene expression domains remain, despite severe head truncation; and the hindbrain/otocyst relationship is altered.
To study the mechanism of hyperthermia on the development of the rostral neural tube, we used a model in which closely-staged presomite 9.5-day rat embryos were exposed in culture to 43 degrees C for 13 min, and then cultured further for 12-48 hr. This treatment had little effect on the development of the rest of the embryo, but resulted in a spectrum of brain defects, the most severe being a lack of all forebrain and midbrain structures. Whole-mount in situ hybridisation was used to monitor the expression domains of Otx2, Emx2, Krox20, and hoxb1. These showed that there were no ectopic expression patterns, for any gene at any stage examined. Even in those embryos which apparently lacked all forebrain and midbrain structures, there were expression domains of Otx2 and Emx2 in the most rostral neural tissue, and these retained their nested dorso-ventral boundaries, showing that cells fated to form rostral brain were not wholly eliminated. Thus, heat-induced rostral neural tube truncation is of a quite different mechanism from the respecification proposed for retinoic acid, despite their very similar phenotypes. In the hindbrain region of treated embryos, we observed decreased intensity of Krox20, staining and an abnormal relationship developed between the position of hoxb1 expression and the otocyst and pharyngeal arches. In the most extreme cases, this domain was shifted to be more caudal than the rostral edge of the otocyst, while the otocyst retained its normal position relative to the pharyngeal arches. We interpret this as a growth imbalance between neuroepithelium and overlying tissues, perhaps due to a disruption of signals from the midbrain/hindbrain boundary.
Animals↗
Clinical anatomy of the atrial septum with reference to its developmental components.
Knowledge of development is of crucial importance and can help clarify mechanisms of maldevelopment, but it must be properly validated. Concepts of development must be consistent with the anatomy seen in postnatal life. Such consistency is not always achieved. We have reviewed new and old accounts of cardiac embryology with regard to the definitive structure of the atrial septum. The key to understanding is to distinguish between folds of the atrial wall and true interatrial partitions. The flap valve of the oval foramen, and its inferior rim, are true septal structures, whereas the other rims, particularly the antero-superior rim, are infoldings enclosing extracardiac fat. During embryonic life, the systemic venous tributaries must achieve entrance only to the right side of the primary atrium. Development of the pulmonary venous component is a late event, with the canalizing vein using the dorsal mesocardium to gain access to the left side of the atrium. Once the systemic venous tributaries have achieved their rightward shift, the primary septum, together with the mesenchymal cap, grows between the systemic and pulmonary venous orifices. Closure of the primary foramen is achieved by fusion of the mesenchymal cap of the primary septum with the atrioventricular endocardial cushions and the vestibular spine (an additional mesenchymal structure carried on the right side of the pulmonary venous orifice). The superior margin of the newly formed secondary foramen is produced by an infolding of the atrial walls. Historically these mechanisms received appropriate recognition, but not all receive their proper due in current writings.
Endocardium↗
Lamivudine therapy of chronic hepatitis B.
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Antiviral Agents↗
Quantitation of hepatitis B viremia and emergence of YMDD variants in patients with chronic hepatitis B treated with lamivudine.
Hepatitis B viremia and emergence of hepatitis B virus (HBV) YMDD variants with reduced susceptibility to lamivudine were analyzed in patient sera from a phase II study of extended lamivudine therapy. Within 12 weeks, all patients exhibited a marked virologic response to lamivudine: >99% reduction (median 5 log decrease) in serum HBV DNA levels. Virus remained at >104 genomes/mL in 11 patients and decreased to <104 genomes/mL in the remaining 12 patients. In 10 patients, detectable YMDD variants emerged during the course of treatment. Six patients, including 3 with YMDD variants, experienced hepatitis B e antigen seroconversion while on lamivudine therapy or soon after its discontinuation. No patients with HBV DNA levels >104 genomes/mL seroconverted. Thus, patients who respond to lamivudine therapy with dramatic reductions in viral DNA level (to <104 genomes/mL) appear more likely to seroconvert than patients who do not achieve this level of HBV clearance.
Antiviral Agents↗
Waves of mouse Lunatic fringe expression, in four-hour cycles at two-hour intervals, precede somite boundary formation.
During somitogenesis, cells are recruited to the caudal presomitic mesoderm (PSM) from the primitive streak (and later the tail bud), while somites separate from the rostral end as epithelial cubes. This is a regular process, one somite forming every 2 hours in the mouse, that can be simulated by clock and wavefront models. The chick basic helix-loop-helix transcription factor encoded by c-hairy1 is expressed in dynamic waves in the PSM, undergoing one cycle for each somite formed. This is compatible with an underlying oscillating molecular clock. We have shown here that Lunatic fringe (L-fng) expression is indicative of it being one of the implementing outputs of this clock. Fringe genes regulate the Notch signalling pathway in boundary formation. Of the known mouse genes, only L-fng is expressed in PSM and it is required for somite segmentation and patterning. We have now shown that L-fng is expressed as dynamic, repetitive and complex waves within the mouse PSM. A wave takes 4 hours to complete one cycle and terminates immediately at, and prior to, somite boundary formation. Consecutive waves are temporally but not spatially overlapping, being initiated in the caudal PSM every 2 hours, so offset by one half-cycle. Waves of expression are not associated with cell movement and do not require cell contact for propagation, so appear to reflect a cell-autonomous clock that is synchronous in all PSM cells.
Animals↗
Formation of the atrioventricular septal structures in the normal mouse.
It is sometimes thought that formation of the atrioventricular septum is equated with fusion of the endocardial cushions and that failure of fusion can explain all deficiencies of atrioventricular septation. Clearly, this is simplistic, but the exact contribution of different primordia to atrioventricular septation is not well understood. To clarify this, we studied normal mouse embryos (days 10 to 15 of gestation), which were serially sectioned and examined by light microscopy. Another group of embryos was examined by scanning electron microscopy after microdissection. Our results show that development of the atrioventricular septal area is highly complex. Proper formation requires the following: remodeling of the inner heart curvature, rotation of the horns of the systemic venous sinus around the pulmonary portal, expansion of the right atrioventricular junction, formation of the muscular atrial and ventricular septa, bridging by the dextrodorsal outflow ridge and the superior endocardial cushion, fusion with the inferior margins of the venous valves, and formation of the mouth of the coronary sinus from the cranial muscular wall of the left sinus horn. Multiple primordia contribute to a central mesenchymal mass (the "septum intermedium"), including the mesenchyme on the leading edge of the primary atrial septum, the atrioventricular endocardial cushions, and the cap of mesenchyme on the spina vestibuli. Fusion of these components closes the ostium primum, completing atrial and atrioventricular septation. Additionally, the spina vestibuli has a mesodermal core, which contributes to the muscularization of the lower margin of the oval fossa. This contrasts with the formation of the upper rim, which occurs as a result of an infolding of the atrial wall itself.
Animals↗
Development of the murine pulmonary vein and its relationship to the embryonic venous sinus.
BACKGROUND: Arguments concerning the development of the pulmonary vein, and its relationship to the embryonic venous sinus (sinus venosus) have continued for well over a century. Recently, attention has again been focused on the origin of the pulmonary vein. It has been suggested that, whereas the pulmonary vein originates from the left atrium in humans, in all other vertebrates it originates from the venous sinus, with subsequent transfer to the left atrium. The nature of this transfer has not, however, been elucidated, although there is speculation that the pulmonary vein is "pinched off" from the left side of the embryonic venous sinus. METHODS: We studied closely staged hearts of normal mouse embryos from a C57BL/6 x CBAcross days 10 and 11 of gestation (plug day = day 1). Two series of embryos were collected and fixed in 2% glutaraldehyde, 1% formaldehyde, buffered with 0.05 M sodium cacodylate pH 7.4 (adjusted to 330 mOsm with NaCl). One series was wax embedded, serially sectioned, and stained with Masson's trichrome. The second series was subject to microdissection and scanning electron microscopy. RESULTS: The atrial component of the heart tube is attached to the body of the embryo by reflections of the atrial myocardial wall. The attachment can be considered, from the outset, as the heart stalk, with the myocardial-mesodermal connections forming a horseshoe of tissue that projects ventrally into the lumen of the atrium, surrounding a single evagination in the midline of the embryo. This heart stalk is cranial to the connections of the tributaries of the embryonic venous sinus and ventral to the foregut. When traced through its developmental stages, the evagination in the centre of the stalk, which we describe as the pulmonary pit, is seen to become the portal of entry for the developing pulmonary vein. CONCLUSIONS: The heart stalk, representing the area used by the pulmonary vein to gain access to the heart, and analogous to the dorsal mesocardium, is, from the outset, discrete from the area occupied by the orifices of the horns of the embryonic venous sinus. The pulmonary vein does not, in the mouse, develop from the tissues that form the walls of the tributaries of the systemic venous sinus. Comparisons with other studies suggest that early events in the development of the pulmonary vein are likely to be the same in all mammals, including humans.
Animals↗
Left-right development: mammalian phenotypes and conceptual models.
Consistent left-right asymmetry in a population requires a special kind of developmental specification. Models of this process must account for the complex phenotypes seen when left-right is abnormal. In some human and mouse mutations, there appears to be a randomisation of global situs to either solitus or inversus, whereas in the inv/inv mouse essentially all are inversus. However, in these and all additional examples there are frequently other anomalies, including symmetry (isomerism) and discordance between organs (heterotaxia). Current models invoke a molecular chiral referent as the source of the primary handed information. We describe a new two-gradient model which accommodates all defects of situs whilst leaving the primary asymmetry unaltered.
Animals↗
The mouse with trisomy 16 as a model of human hearts with common atrioventricular junction.
OBJECTIVE: To establish if the mouse with trisomy 16 is a suitable animal model with which to elucidate the development of a common atrioventricular junction. METHODS: The junctional morphologies in the normal human heart and those with a common atrioventricular junction are compared and contrasted. These are then related to observations made in normal mice and those with trisomy 16. So as better to understand development, a full description is given first of the normal atrioventricular junctions. Developmental implications are discussed because failure of fusion of the endocardial cushions cannot account for all the anomalies found in RXR alpha knockout, and in iv/iv mice. RESULTS: Mice with trisomy 16 showed evidence of deficiencies of atrioventricular septation and possessed a common atrioventricular junction, but the valvar orifices were not balanced between the ventricles as is the case in humans. Whilst some mice showed affinities with human tricuspid atresia, other cardiac malformations in the mice had no counterparts in human cardiac pathology. In humans both "partial" and "complete" forms of "atrioventricular canal malformations" share a basically common muscular junctional morphology, the differences being due exclusively to the way the bridging leaflets are fused to each other and/or the septum. CONCLUSIONS: It is simplistic to use the mouse with trisomy 16 as a model for cardiac abnormalities seen in humans. A spectrum more comparable to humans is found in RXR knockout mice. Study of the iv/iv mouse may help elucidate the genetic steps involved in normal and abnormal atrioventricular septation.
Animals↗
The telemedicine information exchange: an online resource.
Telemedicine is the use of telecommunications to provide health care services at a distance. It has grown from mostly government-subsidized research initiatives into a fledgling industry. This growth was fueled by decreasing costs of telecommunications and information technologies and fanned by rising health care costs. The telemedicine information exchange (TIE) (http:(/)/tie.telemed.org), developed by the Telemedicine Research Center in Portland, OR, is both a product and a vehicle of this rapid growth. It facilitates collection of telemedicine information from many sources, providing an easy-to-use hypertext format. This article describes the TIE's development, advantages and disadvantages of a web-based online library, and it's codevelopment with a rapidly expanding industry.
Costs and Cost Analysis↗
Human D2 and D4 dopamine receptors couple through betagamma G-protein subunits to inwardly rectifying K+ channels (GIRK1) in a Xenopus oocyte expression system: selective antagonism by L-741,626 and L-745,870 respectively.
To examine the effects of a novel selective D4 receptor ligand, L-745,870 (3-[4-(4-chlorophenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyrid ine), on human dopamine receptor function, the ability of this ligand to antagonise G-protein gated inwardly rectifying K+ (GIRK/Kir3) currents activated by cloned human D2 and D4 receptors expressed in Xenopus oocytes was examined using voltage-clamp recording. Its effects were also contrasted with that of a selective D2 receptor antagonist L-741,626. L-745,870 had no detectable agonist activity on human D4 receptors and selectively blocked currents activated by D4 but not D2 receptors. The role of G-protein subunits in dopamine receptor modulation of GIRK currents was also examined by co-expression of beta1 and/or gamma2 subunits on spontaneously active and receptor-activated currents. Currents activated by both D2 and D4 receptors were occluded by direct activation of GIRK currents following co-transfection with the cDNA encoding G-protein betagamma subunits. These data demonstrate that L-745,870 and L-741,626 act as antagonists on human D4 and D2 receptors respectively, and that activation of GIRK channels by these dopamine receptors can be disrupted by direct stimulation of K+ currents by G-protein betagamma subunits.
Dopamine Antagonists↗
Regulation of serotonin re-uptake transporter mRNA expression by ovarian steroids in rhesus macaques.
It has been widely hypothesized that the ovarian steroids, estrogen (E) and progesterone (P), act on serotonin neurons to modulate mood and increase prolactin secretion in women. However, information is needed on the molecular consequences of ovarian hormone action in serotonin neurons. This study examined the effect of E and P on the expression of mRNA for the serotonin re-uptake transporter (SERT) in monkeys using in situ hybridization and a 253 bp human SERT cRNA probe. Monkeys (n=5 animals/group) were ovariectomized and hysterectomized (spayed) and then untreated (control), or treated, with E for 28 days (E treated) or treated with E for 28 days and supplemented with P for the last 14 days of the E regimen (E+P treated). Densitometric analysis of autoradiographs with gray-level thresholding was performed at five levels of the dorsal and median raphe. The number of pixels exceeding background in defined areas was obtained (pixel number). The average pixel number for spayed, E- and E+P-treated groups was 22 280+/-3517, 15 227+/-1714, and 14 827+/-2042, respectively, in the combined dorsal and median raphe. In the E- and E+P-treated groups compared to the control group, there was a 32% and 33% decrease in SERT mRNA signal represented by pixel number (ANOVA, P<0.05). Hence, E- and E+P-treated groups were significantly less than the control group, but they were not different from one another. Also, there were significantly fewer SERT mRNA-positive cells in the dorsal raphe of E- and E+P-treated groups (ANOVA, P<0.001). Therefore E, with or without P, reduces SERT mRNA expression. These results suggest that the ability of P to increase prolactin secretion in E-primed monkeys does not involve an action at the level of SERT gene transcription. Hence, the mechanism by which the CNS transduces the action of P on prolactin secretion remains to be elucidated. However, these data suggest that one action of E replacement therapy in postmenopausal women may be to decrease expression of the SERT gene.
Animals↗
Effects of pulsed ultrasound on embryonic development: an in vitro study.
Whole-embryo culture was used as the model system to study the effects of pulsed ultrasound on embryonic development. Rat embryos (9.5 days old) were exposed to a wide range of ultrasound levels at ultrasound frequencies between 1-4 MHz for 30 min in vitro. After 48 h in culture, absolute control, sham and treatment embryos were assessed for viability, morphology, growth and development. At an ambient temperature of 37 degrees C, no significant effects were observed for spatial peak temporal average intensities below 4 W/cm2 or peak negative pressures below 1.9 MPa. At higher acoustic levels, there was a significant increase in the number of nonviable embryos and the number of morphological abnormalities in viable embryos increased. Abnormal cephalocaudal flexion and abnormal head development were the most common gross morphological abnormalities. Both thermal and nonthermal bioeffect mechanisms are involved.
Analysis of Variance↗
The role of the brachyury gene in heart development and left-right specification in the mouse.
The midline has a theoretical role in the development of left-right asymmetry, and this is supported by both genetic analyses and experimental manipulation of midline structures in vertebrates. The mouse brachyury (T) gene encodes a transcription factor which is expressed in the developing notochord and is required for its development. T/T mice lack a mature notochord and have a dorsalised neural tube. We have examined the hearts of T/T mice and have found consistent morphological abnormalities, resulting in ventrally displaced ventricular loops, and a 50% incidence of inverted heart situs. Three TGF-beta related genes, lefty-1, lefty-2 and nodal, are expressed asymmetrically in mouse embryos, and are implicated in the development of situs. We find that nodal, which is normally expressed around the node and in left lateral plate mesoderm in early somite embryos, is completely absent at this stage in T/T embryos. In contrast, lefty-1 and lefty-2, which are normally expressed in the left half of prospective floorplate and left lateral plate mesoderm, respectively, are both expressed in T/T embryos only in a broad patch of ventral cells in, and just rostral to, the node region. These results implicate the node as a source of instructive signals driving expression of nodal and lefty-2 in the left lateral plate mesoderm, and being required for normal looping and situs of the heart.
Animals↗
Defective lateralisation in children with congenitally malformed hearts.
Defects in lateralization can be studied from the stance of populations, the individual, or the systems of organs within each individual. Unfortunately, and confusingly, the same terms are being applied to each of these situations, but inevitably with different meanings. Thus, there is presently no consensus on how we should use terms such as "heterotaxy" and "situs ambiguus". By far the least ambiguous use of these words is encountered when they are applied to the organs. In fact, each system of organs can accurately and simply be described in terms of its left-right morphology. All those organs which are paired then can be described, when interpreted on the basis of their intrinsic morphology, as being usually arranged, mirror-imaged, or as showing left or right isomerism. Within the heart, these changes are seen only in the atrial segment. The criterion for distinction of rightness or leftness within the atrial segment is the extent of the pectinate muscles relative to the atrioventricular junction. Application of this criterion permits unequivocal recognition of symmetry as opposed to lateralization. The same holds good for the other organs. Within any individual organ, therefore, the situation is neither ambiguous nor heterotaxic. Instead, it is lateralised or symmetrical. Within the individual, in contrast, there may well be discrepancies in the expected disposition of the systems of organs which produces potential ambiguity. To dispel this ambiguity, it is necessary to provide a full catalogue. For example, persons with otherwise normally arranged organs may have left bronchial isomerism. Other persons may have discordance between the thoracic organs, which are usually arranged, and the abdominal organs, which are mirror-imaged, but no evidence of isomerism. Within the population, however, we are unaware of any genetically or environmentally induced syndrome in which all individuals show evidence of mirror-imagery, or of isomerism, or of specific discordance between the systems. In fact, all known syndromes encompass all types of defective lateralization. When attempting to identify the genetic mechanisms for production of the syndromes, therefore, it could be positively misleading to attempt to separate isomerism from other perceived forms of"heterotaxy". Our preference is to consider any deviation from the usual arrangement as heterotaxy, and to specify the specific arrangement of the organs within each malformed individual.
Child↗